3rd International Symposiumfor Medicinal Sciences

CONTENTS
1

Welcome Message 22

Notice for the Presenters and Attendants to the 3rd International Symposium for Medicinal Sciences 3

3Programs at a Glance 

6

4

Access and Venue Map 

125Program of 3rd International Symposium for Medicinal Sciences 18

6Abstracts 

24Appendix
Abstracts Presented by English in 137th Annual Meeting of the Pharmaceutical Society of Japan
1. Programs 50

2. Abstracts 

63

–1–

1

Welcome Message

It is my great pleasure to hold the 3rd International Symposium for Medicinal Sciences in the 137th Annual Meetingof Pharmaceutical Society of Japan. The objectives of this symposium are to encourage pharmaceutical company
researchers who are interested in drug discovery, to participate in this annual meeting, and also to create an importantinternational platform for all those interested in the medicinal sciences. Since this symposium covers the entire drug
discovery field, we welcome participants including pharmacology, pharmacokinetics, and regulatory sciences.
The one of the feature of this symposium is an invited poster presentations. Since high-caliber presentations from theJapanese and foreign pharmaceutical industries, venture companies, and academia will line up in this presentation,
domestic young researchers who interested in the drug discovery, will have a good chance to discuss with the firstclass researchers for drug discovery around the world.
Chairman of the 3rd International Symposium for Medicinal Sciences
Professor Akira OTAKA(Institute of Biomedical Sciences and Graduate School of
Pharmaceutical Sciences, Tokushima University)

Notice to the Foreign ParticipantsThis Abstract is contained all programs which will be presented by English in 137th Annual Meeting of thePharmaceutical Society of Japan other than 3rd International Symposium for Medicinal Sciences, as an appendix.
The appendix was involved the list of the programs and abstracts presented in English, including Special lectures,
Symposia, and general oral and poster presentations.

–2–Notice for the Presenters and Attendants to the 3rd International

2 Symposium for Medicinal Sciences
1) Registration

The program & abstract book, conference ID/registration certificate will be handed at the registration desk, locatedon the foyer, 2nd floor of Exhibition Building, Sendai International Center.
Registration Desk for Overseas participants will open during the meeting.
Registration Fee
Delegate:

JPY 15,000

Student:

JPY 5,000

Undergraduate student:* Free*U ndergraduate students will be required to present their student ID or student certificate letter at theRegistration Desk onsite.
Registration Fee includes
Admission to all scientific sessions
Admission to exhibition and posters
Meeting program & abstract book
BanquetDate and Time:

18:30, Sunday, March 26

Venue:

Room “Sendai” (4th floor), Hotel Metropolitan Sendai

Fee:

JPY 15,000

Banquet tickets can be purchased at the registration desk.

2) General Information[Name badge]	Upon registration all participants will receive a name badge, which must be worn visibly for the entire durationof the meeting. Your name badge acts as your entrance ticket for the meeting.
[Message board]	A message board will be placed near the registration desk. Participants can exchange messages through theboard.
[Camera, Mobile Phone and Video Recording Policies]
Attendees may not take photos or video of speakers presenting or their slides.

3) Area Map and Venue
See page 12-17–3–4) Guideline for Plenary Lectures– Plenary lecturers have 60 minutes (including Q&A).
– The session room only supports digital presentations using only one LCD projector.
– Please bring your power point file in a USB memory or PC to the speakers’ desk before your session, anddownload/check your presentation data.
– The speakers’ desk will be placed in the foyer, 2nd floor of Conference Building.
– A Windows PC (with Windows 7, PowerPoint 2007, 2010, 2013, 2016) is available. If you are a Macintosh user
or wish to use moving images, please bring your own PC. Please make sure to bring an AC adapter, when you
bring your PC.
– Your PC will be connected to the projector with a “15-pin, mini D-sub” cable. Some PCs (Macintosh or thinlaptops) will require a conversion adapter.
– Please turn off the screen saver, power save mode.
– Set the resolution to XGA (1,024×768).
– After you finish your presentation, please receive your PC immediately inside the room.
– The organization committee will be responsible for deleting all copied data.

5) Guidelines for Poster Presentations< Short Oral Presentation >– You will be asked to make a short presentation (strictly 2 minutes).
Session Room: Room B “Tachibana Conference Hall”, 2nd floor of Conference Building
Presentation Time: 14:20-16:00– Please bring your power point file in a USB memory to the speakers’ desk until 13:00 on the day of yourpresentation, and make sure to check the presentation data. A Windows PC (with Windows 7, PowerPoint 2007,2010, 2013, 2016) is only available.
– The speakers’ desk will be placed in the foyer, 2nd floor of Conference Building.
< Poster Presentation >– Poster session room is located in Room G “Meeting Room 4” and the foyer, 2nd floor of Conference Building.
Abstracts scheduled for presentation in poster session will appear in the Symposium Program. Please refer to thetable below for setup, tear down, and presentation times for posters:

Set-Up8:30-9:00
11:45-13:15

Discussion Time

16:00-17:40
Odd Number: 16:00-16:50
Even Number: 16:50-17:40

Tear Down

17:40-18:00–4–

– Each poster board is labeled with a number and check your poster number.
The poster board surface area is 2.1 m high by 1.2 m wide. Each poster should indicate the title ofpresentation, name of authors and affiliations. Text should be printed in a font large enough to be read
comfortably from a distance of 4-5 feet (1.5m).

"recommended usable area"“160×110cm”– Posters should be displayed on the boards using pushpins that will be available at the Poster Session room. No
other adhesive method is permitted on the boards.

–5–

3 Programs at a Glance

24 March (Fri) 25 March (Sat)
Sendai International Center

Sendai International Center

Conference Bldg

Conference Bldg
Room A

Room A

Room B

2F
Main Hall

Main Hall

8:45

8:45

9:00

9:00

9:15

9:15

9:30

9:30

TachibanaRoom D

9:45

9:45

10:00

10:00

10:15

10:15
10:30

Award Lectures

AL-1

Hagi

Room F

Room H

Room I
1F

Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2

Room PA

Room PB

Room J

Room K

2F

1F

SakuraExhibition Hall Meeting Room 1 Meeting Room 2

Symposium

Symposium

Symposium

Let’s challenge New approaches
practicalof exploratory
evidencestudy forbased medicine preventive andeducational
therapeutic
program fortargets inpharmacy
neurodegenerative
Award Lectures students andand psychiatricpharmacists
disorders

How do we
promoteresearch
integrity?

Risk
assessment andmanagement ofa small amountof carcinogens
possibly
exposed in ourordinary life

S01

PL

Naoto OKU

Room E
3F

Symposium

Plenary Lecture

10:30

Room C

2F

Exhibition Bldg

S02

S03

AL-10

Oral
Presentations

Oral
Presentations

Oral
Presentations

25F-am01～
25F-am13

25H-am01～
25H-am13

25I-am01～
25I-am13

Toshihide
TAKEUCHI

PosterPresentations

PosterPresentations

25PA-am001～
25PA-am140

25PB-am001～
25PB-am228

S04【Discussion】 【Discussion】
Odd No.
Odd No.
9:45~10:45
9:45~10:45
Even No.
Even No.
10:45~11:45
10:45~11:45

10:45

10:45

11:00

11:00

11:15

11:15

11:30

11:30

11:45

11:45

12:00

12:00

12:15

12:15

Luncheon Seminar

Luncheon Seminar Luncheon Seminar

Luncheon Seminar

Luncheon Seminar Luncheon Seminar

12:30

12:30
12:45

CRECON
Chugai
MEDICAL
Pharmaceutical
ASSESSMENT
Co., LTD.
INC.

Agilent
Technologies
Japan, Ltd.

Kyowa Chemical
Industry Co., Ltd.

12:45

Japan EMF
Information
CenterOno
PharmaceuticalCo., Ltd. /AstraZeneca K. K.

13:00

13:00

13:15

13:15

13:30

13:30

Symposium

Symposium

13:45

GeneralAssembly

Takeo
KAWABATAAward Lectures

AL-11

HirotoHATAKEYAMA
11:36

LS01

AL-2

Hiroki
SHIGEHISA

Kazuki SAITO

14:15

14:15

14:30

14:30

14:45

14:45

15:00

15:00

15:15

15:15

15:30

15:30

15:45

15:45

16:00

16:00

Award Lectures

AL-13

Taniyuki
FURUYAMA

14:40

Special Lectures

SL-1

Hiro-oHAMAGUCHI

Symposium

S08

16:15

AL-3

Hideo SAJI

16:30

16:45

16:45

17:00

17:00

17:15

17:15

17:30

17:30

17:45

17:45

18:00

18:00

LS05

GS01

Award Lectures

AL-5

MasaakiKURIHARAAward Lectures
Award Lectures

16:30

Symposium

S09

Effective
State-of-theThe front
communication art technology
line and new
betweenby young
progress inpharmacists
neuroscientists cardiovascularand foreign
researchpatients at-Searching for
medical teambreakthroughin treatments ofcardiovasculardisease-Symposium

16:15

Symposium

LS04

LS06

AL-12

13:45
14:00

LS03

11:36

Award Lectures
Award Lectures

14:00

LS02

11:36

AL-6

S15

Symposium

S16

S10

Oral
Presentations

Oral
Presentations

Oral
Presentations

25F-pm01～
25F-pm17

25H-pm01～
25H-pm17

25I-pm01～
25I-pm17

Symposium

GS02

Challenges
Fascination
The challenge
Hidetoshi
to improveof sacran, aof young
ARAKAWAthe prdiction
polysaccharide
researchers
accuacy of the from Aphanotheceleading the
16:35
non-clinical tests
sacrumfuture and16:39
for human CNS
development
adverse effects:of thePotentials
pharmaceutical
16:50
of artificial
research on
intelligenceandcancerAward Lectures
human ESC/iPSC-derived
Takashineurons
SUZUKI

AL-7

17:40

E : English Presentation–6–

PosterPresentations

PosterPresentations

25PA-pm001～
25PA-pm132

25PB-pm001～
25PB-pm307【Discussion】 【Discussion】
Odd No.
Odd No.
14:15~15:15
14:15~15:15
Even No.
Even No.
15:15~16:15
15:15~16:15

Problem-SolvingPartnership
Type Program for for NTDs drug
the Development
discoveryof Highlyoriginated in
Skilled Human
Japan
Resources(- Project for
Nurturing
Pharmacists who
Provide TeamBased Community
Healthcare -)Symposium

Symposium

Current statusof reverse
translational
research
conducted
by hospital
pharmacists

How can the
researchers inuniversity beinvolved withthe streamof hospital
preparations
from themedical needs
to the clinicalapplication?

S17

16:39

16:39

S11

S18

Tohoku University Kawauchi-Kita Campus

Sendai International Center

TohokuUniversity
Multimedia Education andExhibition Bldg Centennial Hall Research Complex

Lecture Rooms C

Room L

Room M

Room N

Room O

1F

2F

2F

2F

Meeting Room 3 Kawauchi Hagi Hall Multimedia Research Hall Lecture room

Room P

Room Q

Room R

Room S

Room T

Room U

1F
C101

C102

Room V

Room W

Room X

2F
C105

C106

C201

C202

Room Y
3F

C205

C206

C301

C302

8:45
9:00
9:15

Symposium

Symposium

Symposium

Utilizing soft
molecularsystems for
drug discovery
research ~theconcerteduse of theory,
measurements
and functional
design~Research
strategies
for the postgolden-age
GPCR drug
discovery

Role of pharmacy
in the promotionof drug safety inpharmacotherapy

S05

S06

S07

9:30
9:45
Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

10:00

25P-am01～
25P-am13

25Q-am01～
25Q-am13

25R-am01～
25R-am13

25S-am01～
25S-am13

25T-am01～
25T-am13

25U-am01～
25U-am13

25V-am01～
25V-am13

25W-am01～
25W-am10

25X-am01～
25X-am13

25Y-am01～
25Y-am13

10:15
10:30
10:45
11:00
11:15

11:36

11:36

11:36

11:36

11:36

11:36

11:36

11:36

11:36

11:30
11:45

Award Lectures

AL-20

12:00

Naomi KURATA

Luncheon Seminar

12:15

SEED Co., Ltd.

12:30

LS07

12:45
13:00
13:15
13:30
Symposium

S12

Structural
biology of lipidbinding proteins-Recent
developments-

Symposium

S13

Young
innovators
driving the next
generation ofacademic drug
discovery

Symposium

S14

13:45

New Trendsof Natural
Products
Chemistry ―Redesign of
Biosynthesis

14:00
14:15
14:30
Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

25P-pm01～
25P-pm16

25Q-pm01～
25Q-pm17

25R-pm01～
25R-pm17

25S-pm01～
25S-pm16

25T-pm01～
25T-pm16

25U-pm01～
25U-pm17

25V-pm01～
25V-pm17

25W-pm01～
25W-pm15

25X-pm01～
25X-pm17

25Y-pm01～
25Y-pm17

14:45
15:00
15:15
15:30
15:45

Symposium

Symposium

Symposium

Scientific basisof plasmaand mechanobiology indiseasetherapy anddrug delivery
towards clinicalapplications

Young
Challengers
in Synthetic
Organic
Chemistry:
DeeperUnderstanding
and Recent
Advancement
in Synthetic
Organic
Chemistry

Modifiednucleic acids
and regulation 16:27
of diseases

S19

S20

S21

16:00

16:03

16:15
16:27

16:27

16:30
16:39

16:39

16:39

16:39

16:39

16:39

16:45
17:00
17:15
17:30
17:45
18:00

–7–

26 March (Sun)Sendai International Center
Conference Bldg
Room A

Room B

Room CRoom D

2F
Main Hall

Room E

Room F

Exhibition Bldg
Room H

3F

Tachibana

Hagi

Room I

Room G

1F

Room PA

Room PB

Room J

Room K

2F

Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2 Meeting Room 4

Room L

1F
SakuraExhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3

8:45
9:00

E

9:15
Special Lectures
9:30

SL-2

Eric KOOLAward Lectures

AL-18

Tomokazu
YOSHINAGA
9:40

Award Lectures

10:00

AL-19
Nobuhiro
OIKAWA

10:15

10:25

SL-3

Takuzo AIDA

11:00
11:15

12:15

10:40

AL-15

Kazuya NAGANO
10:10

Symposium

Symposium

Symposium

Recentadvancesin clinicalchemistry fordeveloping
novel drug
treatment
strategies

Frontier oftranslational
researchby young
investigators
aim to innovative
drug discovery
and drug
fostering

Creation ofComplex
Functional
Molecules
by Rational
Redesign of
Biosynthetic
Machineries

Appropriate
The structuralplanning andstudies ofmanagement
membraneof annual
proteins bymeeting forleading edge
all attendees;
technologies:
application of their forthcoming
active learning contribution topharmacology
and drugdevelopment

S22

GS03

OS23

Oral
Presentations

Oral
Presentations

Oral
Presentations

26F-am01～
26F-am13

26H-am01～
26H-am13

26I-am01～
26I-am13

PosterPresentations

PosterPresentations

26PA-am001～
26PA-am140

26PB-am001～
26PB-am335【Discussion】 【Discussion】
Odd No.
Odd No.
9:45~10:45
9:45~10:45
Even No.
Even No.
10:45~11:45
10:45~11:45

AL-16

Hideyuki KONISHI

E 10:50

International
Symposium
for Medicinal Award Lectures
Sciences

ISMSPL01

11:30

12:00

Award Lectures

SymposiumAward Lectures
Special Lectures

11:45

Toru
KOMATSU

10:20

10:30
10:45

AL-14

9:40

9:45

E

Award Lectures

S24

Symposium

S25

AL-17

Jun
SHIMOKAWA
11:36

Ross D. KING

11:36

11:36

Award Lectures

AL-4

ShigekiSASAKI

Luncheon Seminar Luncheon Seminar Luncheon Seminar Luncheon Seminar

LS08

LS09

Luncheon Seminar Luncheon Seminar Luncheon Seminar

Thermo Fisher
Scientific

Sawai
Daiichi Sankyo
OtsukaPharmaceutical
Company /PharmaceuticalCo., Ltd.
MitsubishiCo., Ltd.
Tanabe Pharma
Corporation

LS12

LS13

LS14

Symposium

Symposium

Symposium

Symposium

Symposium

PSJ'sorganizational
SriramSUBRAMANIAM approach to thepromotion ofgender equality
14:20

Approachto the Next
Remedy by
Multidiscipline
Researchers-for Responding
to Unmet
Medical Needs-

New
The mechanisms Cutting edge
development of of epileptogenesis of retinal circuit
the risk benefit and the effective
research
communicationintervention
PosterPoster- For safety
strategies in
Presentations Presentations
information to bepediatric andcommunicatedelderly patients
26PA-pm001
26PB-pm001
and understood～～
sufficiently26PA-pm133
26PB-pm312

SCIEX

12:30

Shimadzu
Corporation

LS10

Astellas
Pharma Inc.

LS11

12:45
13:00
13:15
13:30
13:45
14:00

E

International
Symposium
Special Lectures for Medicinal
Sciences
SL-4
Masayuki
YAMAMOTO

14:15

15:00
15:15

E
Special Lectures

SL-5

Ruedi
AEBERSOLD

International
Symposium
for Medicinal
Sciences
ISMS:

E

Poster Short
Presentation

15:30

S29

Oral
Presentations

Oral
Presentations

Oral
Presentations

26F-pm01～
26F-pm17

26H-pm01～
26H-pm17

26I-pm01～
26I-pm17

OS33

Yaichiro
KOTAKE

E 16:10Special Lectures

SL-6

International
educational
trends forpharmaceuticalresearchers in thenext generation

Symposium

S34

16:27

Christina WHITE

16:45
17:00

S31

【Discussion】 【Discussion】
Odd No.
Odd No.
14:15~15:15
14:15~15:15
Even No.
Even No.
15:15~16:15
15:15~16:15

Symposium

AL-8

E

16:00

16:30

S30

Award Lectures FIP forum 2017:

15:45

16:15

GS04

E

14:30
14:45

ISMSPL02

OS28

International
Symposium
for Medicinal
Sciences
16:50
ISMS:
Award Lectures
PosterPresentation

16:39

16:39

International
Symposium
for Medicinal
Sciences
ISMS:
PosterPresentation

AL-9

Mitsuhiro
ARISAWA

17:15
17:30
17:40

17:40

17:45
18:00

E : English Presentation–8–

Symposium

S35

Symposium

S36

Protectioun
Progress of
For promotionof Skin fromhealth careof theDryness andinformation
participation of
UV Radiation
technologies the pharmacist-Approach from- On-site
to homeCosmeticsinflection of the medical care
new information
technologies -Tohoku University Kawauchi-Kita Campus

TohokuUniversity
Centennial Hall Multimedia Education andResearch Complex

Sendai Civic
Auditorium

Lecture Rooms C

Room M

Room N

Room O

2F

2F

2F

Kawauchi Hagi Hall Multimedia Research Hall Lecture room

Room P

Room Q

Room R

Room S

Room T

Room U

1F
C101

C102

Room V

Room W

Room X

2F
C105

C106

C201

C202

Room Y

Room Z

3F
C205

C206

C301

C302

8:45
9:00

E
Special Lectures Symposium

SL-7Alexander
MAKAROV

S26

9:15
Symposium

S27

Currents state
The efforts byand future
pharmacists toprospects of implement home
doctoral course medical care forfor students
heart failure - a
graduatedcomprehensivefrom division of
integrated
pharmacy (4- community care year program)- A survey
Special Lecturescommissioned
to PSJ from theHidenoriMEXTICHIJO

9:30
9:45
Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

10:00

26P-am01～
26P-am13

26Q-am01～
26Q-am13

26R-am01～
26R-am13

26S-am01～
26S-am13

26T-am01～
26T-am13

26U-am01～
26U-am13

26V-am01～
26V-am13

26W-am01～
26W-am12

26X-am01～
26X-am12

26Y-am01～
26Y-am13

10:15
10:30

SL-8

10:45
11:00

11:12

11:15
11:24
11:36

11:36

11:36

11:36

11:36

11:36

11:36

11:30

11:36

11:45
12:00
12:15
12:30
12:45
13:00
13:15
13:30

Special Lectures

Symposium

SL-9

S32

Katsumi
MATSUZAKI

13:45

Forefrontof cancer
targetingtherapy

14:00
14:15
14:30

Special Lectures

SL-10

Keiji
MARUOKA

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

26P-pm01～
26P-pm17

26Q-pm01～
26Q-pm17

26R-pm01～
26R-pm16

26S-pm01～
26S-pm13

26T-pm01～
26T-pm17

26U-pm01～
26U-pm17

26V-pm01～
26V-pm17

26W-pm01～
26W-pm17

26X-pm01～
26X-pm17

26Y-pm01～
26Y-pm11

PublicLecture

14:45
15:00
15:15

15:27

15:30

Symposium

Symposium

Frontiers inimmunology forinnovative drug
development

Frontiers of
Research
on Anti-Viral
Infectious
Diseases16:39
Boundary
between Host
Defense andViral Offense-

S37

15:45

15:51

S38

16:00
16:15
16:27

16:30
16:39

16:39

16:39

16:39

16:39

16:39

16:45
17:00
17:15
17:30

18:30

–9–

Hotel Metropolitan Sendai
Banquet (buffet style)

17:45
18:00

27 March (Mon)
Sendai International Center
Conference Bldg
Room A

Room B

Room CRoom D

Room E

2F
Main Hall

TachibanaRoom F

Exhibition Bldg
Room H

3F
Hagi

Room I
1F

Shirakashi 1 Shirakashi 2 Meeting Room 8 Meeting Room 1 Meeting Room 2

Room PA

Room PB

Room J

Room K

Room L

2F

1F

SakuraExhibition Hall Meeting Room 1 Meeting Room 2 Meeting Room 3

8:45
9:00

E

9:15
Symposium

Symposium

Symposium

Symposium

Recent advances in
DDS research on the
key molecule "cellpenetrating peptides"that controls the
kinetics of the nextgeneration drug target"biopharmaceuticals"

Catalysis
Bridging
Material
Science andLife Science

Lifestyleinspires future
pharmacotherapy
and drug
discovery

PSJ-PSK Joint
RecentVarious
PosterPosterSymposium:
advances inphysiological
Presentations
Presentations The mechanism, the networking
actions
evaluation,and crosstalk
mediated
27PA-am001
27PB-am001
prediction andthroughthrough a Na+/～～
diagnosis ofseveral organs
glucose co27PA-am141
27PB-am255
drug-induced
to affect thetransporter
liver injury
homeostasis of (SGLT) and theliving organism possibility of the【Discussion】 【Discussion】
innovative drug
Odd No.
Odd No.
development
9:45~10:45
9:45~10:45
Even No.
Even No.
10:45~11:45
10:45~11:45

S39

9:30
9:45
10:00
10:15

S40

S41

10:30
10:45

OS42

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

27E-am01～
27E-am09

27F-am01～
27F-am13

27H-am01～
27H-am13

27I-am01～
27I-am13

10:48

11:00

Symposium

S43

Symposium

S44

11:15
11:30

11:36

11:36

11:36

11:45
12:00
Luncheon Seminar

LS15

12:15

Live Cell SuperResolution Imaging
Research TeamRIKEN Center
for Advanced
Photonics

12:30
12:45
13:00
13:15
13:30
13:45

Nobel Lecture
Broadcasting(Live)

Symposium

S47

Symposium

S48

Symposium

Symposium of Frontier of theMetallomic
The Division
middle size
research basedof Physicaldrug discovery- on determining
Sciences of the
Middlethe relationshipPharmaceuticalmolecular
between biometals
Society ofstrategy:
and biologicalJapan
Creationreactions: Fromof higher
investigation of
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molecules
role of biometals
by integrated
to establishment
synthesisof novel
pharmacotherapy
for major diseases

14:00
14:15
14:30
14:45
15:00
15:15

Symposium

S49

S51

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

27E-pm01～
27E-pm1427F-pm01～
27F-pm17

27H-pm02～
27H-pm17

27I-pm01～
27I-pm17

15:30

PosterPresentations

PosterPresentations

27PA-pm001～
27PA-pm136

27PB-pm001～
27PB-pm191

Symposium

S52

Evaluation
Platformand guarantee developmentof quality offor drug
pharmaceutical
discovery
education by
utilizing
the Japan
silkworm
Accreditation towards "Novel
Board forIndustrial
Pharmaceutical
Revolution"
Education【Discussion】 【Discussion】
Odd No.
Odd No.
14:15~15:15
14:15~15:15
Even No.
Even No.
15:15~16:15
15:15~16:15

15:45
16:00

Nobel Lecture
Broadcasting(recorded)

16:15
16:30
16:45
17:00

Symposium

S55

Chemical
Biology for
Pharmaceutical
Sciences(Developmentof practicalchemicalbiotechnology)

Symposium

S56

Frontier ofSynthetic
Organic
Chemistry
Opened by
Precisely
Designed
Catalysts with
Specified Field

Symposium

Symposium

Symposium

Iron Ion as a
New Target for
Drug Discovery

Current trends
in analyticaltechnologies
which promote thedevelopment ofbiopharmaceuticals

An explosion ofphotoswichable
molecules for
spatiotemporalvisualizationand control ofbiological activity

S57

16:03
16:15

16:39

16:39

17:15
17:30
17:45
18:00

E : English Presentation– 10 –S58

S59

Tohoku University Kawauchi-Kita Campus

TohokuUniversity
Centennial Hall Multimedia Education andResearch Complex

Lecture Rooms C

Room M

Room N

Room O

2F

2F

2F

Kawauchi Hagi Hall Multimedia Research Hall Lecture room

Room P

Room Q

Room R

Room S

Room T

Room U

1F
C101

C102

Room V

Room W

Room X

2F
C105

C106

C201

C202

Room Y
3F

C205

C206

C301

C302

8:45
9:00
9:15

Symposium

Symposium

Symposium

Novel
Developmentof Toxicology
Studies ofChemicals

Pharmaceutical
Compounds inthe Environment-Distribution,
Ecological effects,
and Purification
Technologies-

Knowledgeof druginteractions
to takeadvantage inthe pharmacist

S45

S46

S50

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

27P-am01～
27P-am13

27Q-am01～
27Q-am12

27R-am01～
27R-am12

27S-am01～
27S-am12

27T-am01～
27T-am13

27U-am01～
27U-am13

27V-am01～
27V-am13

27W-am01～
27W-am13

27X-am01～
27X-am13

9:30
9:45
10:00
10:15
10:30
10:45
11:00
11:15

11:24

11:24

11:24

11:36

11:36

11:36

11:36

11:36

11:36

11:30
11:45
12:00
12:15
12:30
12:45
13:00
13:15

Nobel
LectureSymposium

Yoshinori
OHSUMI

Frontier
Frontier of
Pharmaceutics tobiomedical
Be Explored byscience by
Young Scientists:biomolecule
Opening Up
analysis based
New Horizon of
on mass
Pharmaceutics for spectrometry
Next Generation
Innovative Drug
Discovery andDevelopment using
Nanoscience andNanotechnology

NL

S53

Oral
Presentations

Symposium

S54

Oral
Presentations
27X-pm01～
27X-pm06

27U-pm01～
27U-pm04

13:30
13:45
14:00

14:03

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations

Oral
Presentations 14:27

14:15

27P-pm01～
27P-pm09

27Q-pm01～
27Q-pm12

27R-pm01～
27R-pm16

27S-pm01～
27S-pm17

27T-pm01～
27T-pm17

27V-pm01～
27V-pm17

27W-pm01～
27W-pm14

14:30
14:45
15:00

15:03

15:15
15:30
15:39

15:45
Nobel Lecture
Broadcasting(recorded)

16:03

16:00
16:15

16:27

16:30
16:39

16:39

16:39

16:45
17:00
17:15
17:30
17:45
18:00

– 11 –

4 Access and Venue Map

Access◆Map

Tohoku Univ.

Kawauchi-Kita Campus

Tohoku Univ. Centennial Hall:

Kawauchi Hagi Hall

Hotel Metropolitan Sendai(Banquet on March 26)

Sendai International Center◆Access
Sendai Airport

By AirSendai Airport Access Line:
17min. - 25min. [650 yen]

ＪＲ Sendai Station（West Entrance）

By Train
TAXI:
12min. [1,200 yen]

Subway Tozai - Line:
6min. [200 yen]

Subway Tozai - Line:

Subway Tozai - Line:

Kawauchi Station
on foot 3min.

Tohoku Univ.

International Center Station

on foot 10min.

Kawauchi-Kita Campus

Subway Tozai - Line:
5min. [200 yen]

TAXI:
10min. [1,000 yen]

on foot 10min.

Tohoku Univ. Centennial Hall:

Kawauchi Hagi Hallon foot 7min.

on foot 3min.

Sendai International Centeron foot 10min.
on foot 15min.

– 12 –

Area Map
The Miyagi Museum of Art
Convenience Store

Tohoku Univ.

Multimedia Research Hall
SubwayKawauchi Station

Tohoku Univ.

Lecture Rooms C

SubwayInternational
CenterStationTohoku Univ. Centennial Hall:

Kawauchi Hagi Hall

Sendai International Center
Tohoku Univ.
Main LibraryP

Conference Bldg.

Ougi-zaka(80-step)

Sendai International Center

Exhibition Bldg.

050

Sendai City Museum

100m

Aoba Castle Facility

Room(Under Construction)

Place

A, B, C, D, E, F, G, H, I, PA

Sendai International Center Conference Bldg.

J, K, L, PB

Sendai International Center Exhibition Bldg.

M

Kawauchi Hagi Hall

N

Kawauchi-Kita Campus: Multimedia Research Hall

O, P, Q, R, S, T, U, V, W, X, Y

Kawauchi-Kita Campus: Kawauchi Lecture Rooms C

Exhibition
Exhibition Room

Place
Sendai International Center Exhibition Bldg. Exhibition Hall 2

Registration
Registration & Information Desk

Place
Sendai International Center Exhibition Bldg. Foyer
Kawauchi-Kita Campus: Kawauchi Lecture Rooms C １F C103
Sendai International Center Conference Bldg. 2F Lobby

PC Center

Kawauchi-Kita Campus: Kawauchi Lecture Rooms C ２F C203
BanquetHotel Metropolitan Sendai 4F「千代（Sendai）」– 13 –

Sendai International Center
Conference Bldg. 1F

EV

Cloak②

Room: H

【Meeting Room 1】

Room: I

【Meeting Room 2】

Reception

EV【Cafe "Leaf"】

Entrance

Conference Bldg. 2F

Room: A

【Main Hall】

Room: PA
【Sakura】

PC Center

2F Lobby

Room: C
【Hagi】

Secretariat【Meeting Room 5】

Room: B【Tachibana】

to Exhibition Bldg.

Room: G

【Meeting Room 4】– 14 –

EV

Conference Bldg. 3F

Room: F

【Meeting Room 8】

Room: D

【Shirakashi 1】

Room: E

【Shirakashi 2】
EV

Exhibition Bldg.
to Conference Bldg. 1FRegistration & Information Desk
Room: L

【Meeting Room 3】

to Conference Bldg. 2F

Lunchtime Seminars Ticket Counter

Exhibition Seminar【Meeting Room 4】

from Subway
International
Center Station

Foyer

Room: K

【Meeting Room 2】

Poster Room Information

Room: J

【Meeting Room 1】

Room: PB

【Exhibition Hall 1】

Cloak①– 15 –

Exhibition Room
【Exhibition Hall 2】

Tohoku University Centennial Hall Kawauchi Hagi Hall

1F

バーコーナーEV

PC Center【1F Lobby】

Entrance

2F
EV

PC Center

Room: M

【Hagi Hall】

Foyer– 16 –

Tohoku University Kawauchi-Kita Campus
Multimedia Education and Research Complex 2F

EV

Room: N【Multimedia Research Hall】【M206】

PC Center
Multimedia Education and Research Complex 1F

EV

Lecture Rooms C 1F

Room: S

Room: R

Cloak③

Room: P

Room: Q

【C103】【C106】【C101】

Lecture Rooms C 2F

【C105】【C102】【C104】

Registration &Information Desk

Room: W

Room: V

C204

Room: T

Room: UPC Center

Room: X

Room: Y【C206】【C205】

Room: O

【Lecture room】【C201】【C202】

Lecture Rooms C 3F

【C301】– 17 –【C302】【C203】

5

Program of 3rd International Symposium for Medicinal Sciences

Sunday, 26 March 10:40 ～ 11:45 / 13:15 ～ 17:40
Plenary Lecture: Room B Tachibana Conference Hall, Sendai International Center (Conference building 2F)

Invited Poster Presentation: Room G Meeting Room 4, Sendai International Center (Conference building 2F)

3rd International Symposium for Medicinal Sciences
10:40 ～ 10:45
Opening Remark 

Chairman: Akira OTAKA（Tokushima University）

10:45 ～ 11:45
Plenary Lecture 1 ISMS-PL01

Chairman: Tsuneaki SAKATA（Shionogi & Co., Ltd.）

Robot Scientists: Automating Drug Design

Ross D. KING（University of Manchester）

13:15 ～ 14:15
Plenary Lecture 2 ISMS-PL02

Chairman: Tatsuhiko KODAMA（The University of Tokyo）

Recent Advances in cryo-EM: Applications to Drug Discovery
Sriram SUBRAMANIAM（National Cancer Institute, NIH）

14:20 ～ 17:40
Invited Poster Presentation
14:20 ～ 16:00

Short Presentation for Invited Poster Presentation

16:00 ～ 17:40

Poster Presentation
Discussion   Odd Number: 16:00 ～ 16:50
Even Number: 16:50 ～ 17:40

26G-ISMS01 Unstructured Protein : A New Approach for Drug Discovery○ Takenao ODAGAMI1, Yoichiro HIROSE1, Yoshimasa IMAMURA1, Akira KATOH1,
Tadashi MISHINA1, Hiroyuki KOUJI1（1Research & Development, PRISM BioLab Co., Ltd.）
26G-ISMS02 Development of Macrocyclic Peptide Targeting Ebola Glycoprotein○ Shiori UMEMOTO1, Junki MARUYAMA2, Ayato TAKADA2, Hiroaki SUGA1（1Department
2of Chemistry, Graduate School of Science, The University of Tokyo, Department of Global Epidemiology, ResearchCenter for Zoonosis Control, Hokkaido University）

26G-ISMS03 Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide
Destruxin B as a Negative Regulator for Osteoclast Morphology○ Hiroshi SATO1,2, Masahito YOSHIDA1, Hayato MURASE3, Hiroshi NAKAGAWA3,
Takayuki DOI1（1Graduate School of Pharmaceutical Sciences, Tohoku University, 2Mitsubishi Tanabe Pharma
Corporation,3

Department of Applied Biological Chemistry, Chubu University）

26G-ISMS04 SAR Exploration of Selective Kinase Inhibitors based on the “Head-to-Tail” Approach:Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds○ Satoru NOJI1, Noriyoshi SEKI1, Takaki MAEBA1, Takayuki SAKAI1, Eiichi WATANABE1,
Katsuya MAEDA1, Kyoko FUKUSHIMA1, Toru NOGUCHI1, Kazuya OGAWA1,
Yukiyo TOYONAGA1, Tamotsu NEGORO1, Hisashi KAWASAKI1, Makoto SHIOZAKI1
1（ Central Pharmaceutical Research Institute, Japan Tobacco Inc.）– 18 –

26G-ISMS05 Search for Anti-leukemic Drugs Targeting the Transcription Factor Runx1 by INTENDD○ Masaaki SHIINA1, Shiho BABA1, Akiko UCHIYAMA1, Chikako OKADA1,
Takeshi TANAKA2, Ken IKEDA2, Shigetsugu KAWAKITA2, Takao MATSUZAKI2,
Hirotsugu KOMATSU2, Masato HOSODA2, Kazuhiro OGATA1（1Yokohama City University,
2

Graduate School of Medicine, Interprotein Corporation）

26G-ISMS06 Evaluation of Novel Anti-Dengue Candidates Using In Silico and In Vitro Approaches○ Yu-Shi TIAN1, Hitoshi MATSUDA2, Xinzhe LIU2, Norihito KAWASHITA2,3,
Tatsuya TAKAGI2,3（1Graduate School of Information Science and Technology, Osaka University, 2Graduate
3

School of Pharmaceutical Sciences, Osaka University, Graduate School of Information Science and Technology,
Osaka University Research Institute for Microbial Diseases）

26G-ISMS07 Development and Construction of an Original Compound Library for CNS Drug
Discovery: Combining Computational and Wet Data to Enhance CNS Drug-likeness○ Daiju HASEGAWA1（1Medicinal Chemistry, Neurology Tsukuba Research Department, Discovery, Medicine
Creation, Neurology Business Group, Eisai Co., Lid.）

26G-ISMS08 Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b ]Pyridazine- based p38 MAP Kinase Inhibitors○ Akira KAIEDA1, Masashi TAKAHASHI1, Takafumi TAKAI1, Masayuki GOTO1,
Takahiro MIYAZAKI1, Yuri HORI1, Satoko UNNO1, Tomohiro KAWAMOTO1,
Toshimasa TANAKA1, Sachiko ITONO1, Terufumi TAKAGI1, Teruki HAMADA1,
Mikio SHIRASAKI1, Kengo OKADA1, Gyorgy SNELL2, Ken BRAGSTAD2, Bi-Ching SANG2,
Osamu UCHIKAWA1, Seiji MIWATASHI1（1Takeda Pharmaceutical Company Limited, 2Takeda
California, Inc.）

26G-ISMS09 Flow Chemistry: New Horizons in Chemical Space for the Creation of Next Generation
Libraries
Daniel BLANCO-ANIA3, Sagar Ashok GAWADE1, Luuk MAARTENSE1,
Roel VERLEIJSDONK1, Remco MERKX2, Huib OVAA2, Floris RUTJES1, Marjon BOLSTER3,
Luc ZWINKELS3, Joeri SCHEIDT3, Pauline van MEURS3, Jorg BENNINGSHOF3,○ Norimasa MORITA3（1Radboud University, 2Leiden UMC (Former NKI), 3Mercachem）
26G-ISMS10 Transition Metal-Free, Tryptophan-Selective Bioconjugation of Proteins○ Kounosuke OISAKI1, Yohei SEKI1, Takashi ISHIYAMA1, Daisuke SASAKI1,2, Junpei ABE1,
Yohei SOHMA1,2, Motomu KANAI1,2（1Graduate School of Pharmaceutical Sciences, The University of
2Tokyo, JST, ERATO Kanai Life Science Catalysis Project）

26G-ISMS11 Total Synthesis of Halichondrin A and C○ Akihiko YAMAMOTO1, Atsushi UEDA1, Paul BRÉMOND1, Paolo S. TISENI1,
Daisuke KATO1, Yoshito KISHI1（1Department of Chemistry and Chemical Biology, Harvard University）
26G-ISMS12 Parallel Fluorescent Probe Synthesis Based on the Large-scale Preparation of BODIPYFL Propionic Acid
○ Taisuke KATOH1, Masato YOSHIKAWA1, Takeshi YAMAMOTO1, Ryosuke ARAI1,
Noriyuki NII1, Yoshihide TOMATA1, Shinkichi SUZUKI1, Ryoukichi KOYAMA1,
Nobuyuki NEGORO1, Takatoshi YOGO1（1Pharmaceutical Research Division, Takeda Pharmaceutical
Company, Ltd）

26G-ISMS13 Improvement in Pharmacokinetics and In Vivo Activity of Somatostatin by Chemical
Glycosylation○ Hirofumi OCHIAI1, Jun IGARASHI1, Hayato SAIJO1, Takahiro YAMAMOTO1,
Yuji NISHIUCHI1, Akio KANATANI1, Taiji SHIMODA1（1GlyTech, Inc.）
26G-ISMS14 Development of an Oxidative Mizoroki-Heck Reaction for Late-stage C-HFunctionalization of Complex Molecules and Application to Pharmaceutical Studies○ Kenji WATANABE1, Amrita DAS1, Takumi KIMIJIMA1, Tomohiro YAMASHITA1,
Kazuhide INOUE1, Makoto TSUDA1, Takashi OHSHIMA1（1Graduate School of Pharmaceutical
Sciences, Kyushu University）– 19 –

26G-ISMS15 Functional Characterization of Acetylcholine Receptors in Human HippocampusDerived Neurons○ Kazuyuki FUKUSHIMA1, Kazuto YAMAZAKI2, Norimasa MIYAMOTO3,
Kohei SAWADA3（1Neurology Tsukuba Research Department, Discovery, Medicine Creation, Neurology
2

3

Business Group, Eisai Co., Ltd., Technology Cross Point Laboratory, hhc Data Creation Center, Eisai Co., Ltd., Global
CV Assessment, BA CFU, Medicine Development Center, Eisai Co., Ltd.）

26G-ISMS16 Analgesic Effect of Novel 11 β -HSD1 Inhibitor ASP3662 and its Mechanism of Action
in a Spinal Nerve Ligation Model of Neuropathic Pain
○ Tetsuo KISO1, Toshihiro SEKIZAWA1, Mina TSUKAMOTO1, Junko YARIMIZU1,
Shuichiro KAKIMOTO1（1Drug Discovery Research, Astellas Pharma Inc.）
26G-ISMS17 Atomic-Scale Investigation on Acetaminophen Crystals with Stable and Metastable
Phases by Frequency Modulation Atomic Force Microscopy in Aqueous Solution○ Naritaka KOBAYASHI1, Kazuki OKANO2, Yoichiro MORI3, Shun FUKUKITA3,
Mihoko MARUYAMA4, Hiroaki ADACHI3,5, Kazufumi TAKANO4,5, Satoshi MURAKAMI5,6,
Hiroyoshi MATSUMURA5,7, Tsuyoshi INOUE3,5, Masashi YOSHIMURA5,8, Yusuke MORI3,5,
Seiichiro NAKABAYASHI1, Hiroshi YOSHIKAWA1,3（1Graduate School of Science and Engineering,
2

3

Saitama University, Faculty of Science, Saitama University, Graduate School of Engineering, Osaka University,
4
5
6
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, SOSHO, Inc., Graduate School
7of Bioscience and Biotechnology, Tokyo Institute of Technology, College of Life Science, Ritsumeikan University,
8
Institute of Laser Engineering, Osaka University）

26G-ISMS18 Anti-inflammatory Flavan-dihydrochalcones with Unprecedented Carbon Skeletonsfrom Daemonorops Draco○ Ping-Chung KUO1, Hsin-Yi HUNG1, Tsong-Long HWANG2, Tian-Shung WU1（1 School of
Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 
2Graduate Institute of Natural Products, College of Medicine, Chang Gung University）

26G-ISMS19 Development of a Fully Automated HPLC System (ASAPrepTM) Designed for Multiple
Compound Purifications○ Chie KUSHIBE1, Katsuhiko MIWA1, Hidetoshi TERADA2, Yuji KATSUYAMA2（1Medicinal
2

Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Life
Science Business Department, Analytical & Measurement Instruments Division, Shimadzu Corporation）

26G-ISMS20 Discovery of a Novel PDE10A Inhibitor as Highly Effective for Schizophrenia○ Yoichi KADOH1, Takehiko MATSUMURA1, Yoshihito TANAKA1, Mitsuya HONGU1,
Haruko MIYOSHI1, Mayumi KIMURA1, Kei TAKEDOMI1, Kenji OMORI1, Jun KOTERA1,Takashi SASAKI1, Kiichi TANAKA1, Keiko MIWA1, Tamaki KOBAYASHI1,
Hiroyuki TANIGUCHI1, Taketoshi ISHII1, Yumi WATANABE1, Haruna ITODA1,
Rikiya OHASHI1, Kouki KOJIMA1, Masaya FUKUDA1, Saori SATO1, Itsuko NAKAMURA1,
Toshiaki SAKAMOTO1, Toshiyuki HIMIYAMA1, Masataka HIKOTA1, Eiji KAWANISHI1
1（ Mitsubishi Tanabe Pharma Corporation）

26G-ISMS21 Nucleic Acid Drugs Large Scale Manufacturing and Specification Assay– Equivalency
Solid Phase versus AJIPHASE® and Oligonucleotide Sequences Confirmation for IND
and NDA○ Satoshi INOUE1, Hirokazu NANKAI1, Emi SAITO1, Hideaki SATO1, Kazuhiko YUYAMA1
1（ GeneDesign, Inc.）

26G-ISMS22 Amycolamicin, a Novel Antibiotic as a Promising Candidate for Clostridium Difficile
Infection: Antibacterial Activity, Mode of Action, and In Vivo Efficacy○ Yoshimasa ISHIZAKI1, Kazushige SASAKI1, Hideki HASHIZUME1, Chigusa HAYASHI1,
Kunio INOUE1, Hayamitsu ADACHI1, Yoshiaki TAKAHASHI1, Masayuki IGARASHI1,
Yoshio NISHIMURA1, Yuzuru AKAMATSU1, Akio NOMOTO1, Masakatsu SHIBASAKI1
1（ Institute of Microbial Chemistry (BIKAKEN)）

26G-ISMS23 Identification and Optimization of a Novel Series of Tetrahydroisoquinoline Derivatives
as an Orally Active MGAT2 Inhibitor○ Tsuyoshi BUSUJIMA1, Hiroaki TANAKA2, Eiji MUNETOMO3, Kiyokazu KITANO3,
Masako SAITO3（1Pharamceutical Science Laboratories, 2Chemistry Laboratories, 3Pharmacology Laboratories,
Taisho Pharmaceutical Co., Ltd.）– 20 –

26G-ISMS24 Discovery of Novel Fluoroquinolone Antibiotics WFQ-101 and Its Optimization Study○ Tatsuya HIRANO1, Tomohiko KINOSHITA1, Daichi KAZAMORI1, Satoshi INOUE1,
Kouji NISHIMURA1, Asuka SAKURAI1, Ayuka SASAKI1, Yasuhiro KURAMOTO1,
Hirotaka AMANO1, Akira YAZAKI1（1Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.）
26G-ISMS25 Anti-CTLA-4 Antibody scFv Producing Recombinant Bifidobacterium Secretes CTLA4 Blocker Specifically Inside Hypoxic Tumor and Suppresses Tumor Growth inSyngeneic Mice Model○ Shiro KATAOKA1, Koichiro SHIOYA1, Li WANG1, Tomio MATSUMURA1,
Hitomi SHIMIZU1, Yasuyoshi KANARI1, Yuji SEKI1, Yuko SHIMATANI1,
Minoru FUJIMORI2, Shun'ichiro TANIGUCHI3（1Anaeropharma Science, Inc., 19-8, Nihonbashi Kabuto2cho, Chuo-ku, Tokyo 103-0026, Japan, Department of Breast Surgery, Tokyo Medical University Ibaraki Medical
3
Center, Ibaraki, Japan, Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine）

26G-ISMS26 Structural Basis for Activation of Neisseria Meningitides Elongation Factor P with
Arginine-32 Rhamnosylation by EarP
○ Toru SENGOKU1（1RIKEN Structural Biology Laboratory）
26G-ISMS27 Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-selective
Noradrenaline Reuptake Inhibitor, Part I -Lead Series Discovery and Biological
Concept Validation○ Ikuo FUJIMORI1, Tomoya YUKAWA1, Taku KAMEI1, Yoshihisa NAKADA1,
Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Maiko TAKIGUCHI1,
Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1, Teruki HAMADA1,
Tomoko IGARI1, Teruaki OKUDA1, Satoshi YAMAMOTO1, Tetsuya TSUKAMOTO1, Yuji
ISHICHI1, Hiroyuki UENO1（1Takeda Pharmaceutical Company Limited）
26G-ISMS28 Design, Synthesis and Biological Evaluation of a Novel Series of Peripheral-selective
Noradrenaline Reuptake Inhibitor, Part II -Lead Optimization with Avoiding P-gp
Substrate and Genetic Polymorphism○ Tomoya YUKAWA1, Ikuo FUJIMORI1, Taku KAMEI1, Yoshihisa NAKADA1,
Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Hiroyuki UENO1,
Maiko TAKIGUCHI1, Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1,
Yasushi FUJIOKA1, Tomoko IGARI1, Yuji ISHICHI1, Tetsuya TSUKAMOTO1
1（ Takeda Pharmaceutical Company Limited）

26G-ISMS29 Ex Vivo Gene-manipulated Mature Adipocytes: Novel Gene Therapy Medicine for
Sustained Protein Replacement Therapy of Variety of Intractable Diseases○ Masayuki KURODA1, Hideaki BUJO2, Koutaro YOKOTE3, Yasushi SAITO4,
Masayuki ASO5（1Center for Advanced Medicine, Chiba University, 2Department of Clinical Laboratory
3

Medicine, Toho University Medical Center Sakura Hospital, Department of Clinical Cell Biology and Medicine,
4
Graduate School of Medicine, Chiba University, Superintendent of the hospital bureau, City Hall of Chiba,
5CellGenTech, Inc.）

26G-ISMS30 Application of Novel Highly Immunodeficient Mice for Patient Derived Xenograft(PDX) Model and Evaluation of Anticancer Therapy○ Seiji OKADA1, Kulthida VAETEEWOOTTACAHRN1, Hiroki GOTO1, Ryusho KARIYA1
1（ Center for AIDS Research and Graduate School of Medical Sciences, Kumamoto University）

26G-ISMS31 The Unbound Concentration of Multimodal Drugs in the Assay Medium Used in theMulti-electrode Array System for Cardiac Risk Assessment with iPS Cell-derived
Cardiomyocytes○ Takashi YOSHINAGA1,4, Raku SINKYO2, Kiyomi KIKUCHI2, Tomohiko TANIGUCHI1,4,
Yuko SEKINO3,4, Kohei SAWADA1,4（1Global CV Assessment, Eisai Co., Ltd., 2Global DMPK, Eisai Co., Ltd.,
3

4

Division of Pharmacology, National Institute of Health Sciences, Japan iPS Cardiac Safety Assessment (JiCSA)）– 21 –

26G-ISMS32 Discovery of ASP3026, a Potent and Selective Anaplastic Lymphoma Kinase (ALK)
Inhibitor○ Kazuhiko IIKUBO1, Yutaka KONDOH1, Itsuro SHIMADA1, Takahiro MATSUYA1,
Kenichi MORI1, Yoko UENO1, Sadao KUROMITSU1, Minoru OKADA1（1Astellas Pharma Inc.）
26G-ISMS33 Immune Profiling with a New NGS-based Repertoire Analysis○ Takaji MATSUTANI1, Kazutaka KITAURA1, Hiroshi YAMASHITA1, Hitomi AYABE1,
Hiroyuki SATO1, Yuichi MORITA1, Tadasu SHINI2,3, Ryuji SUZUKI1,3（1Repertoire Genesis
2

3

Incorporation, BITS. Co., Ltd., Clinical Research Center for Rheumatology and Allergy, Sagamihara National
Hospital）

26G-ISMS34 Cyclodextrin-based Supramolecular Drug Carriers and Active Pharmaceutical
Ingredients○ Taishi HIGASHI1, Keiichi MOTOYAMA1, Hidetoshi ARIMA1,2（1Department of Physical2

Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Program for Leading Graduate
Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University）

26G-ISMS35 Antifungal Activities and Nonclinical Pharmacokinetics of APX001A/APX001 (E1210/
E1211), a New Broad-Spectrum Antifungal, with a New Mode of Action○ Takaaki HORII1（1Global Health Research Section, hhc Data Creation Center, Eisai Co., Ltd.）
26G-ISMS36 Synthesis and Evaluation of Potent, Orally Available, Well-balanced EP2 and EP3 Dual
Agonists○ Akihiro KINOSHITA1, Masato HIGASHINO1, Koji YOSHIDA1, Yoshiyuki ARATANI1,
Akito KAKUUCHI1, Keisuke HANADA1, Hiroyuki TAKEDA1, Toshikiko NISHIYAMA1,
Hidekazu MATSUYA1, Kazuyuki OHMOTO1（1Medicinal Chemistry Research Laboratories, Ono
Pharmaceutical Co., Ltd.）

26G-ISMS37 Novel Development of Chemotherapy for Relapsed and Refractory AML Based on thePromising Functional Mechanism of Cytidine Analog, DFP-10917○ Masakazu FUKUSHIMA1, Kenzo IIZUKA1, Chung ZHANG1, Cheng JIN1, Kiyoshi ESHIMA1
1（ Division of Research and Development, Delta-Fly Pharma, Inc.）

26G-ISMS38 System-wide Temporal Characterization of the Phosphoproteome of Non-small-cell
Lung Cancer Cells Treated with Erlotinib○ Adachi JUN1, Yuichi ABE1, Maiko SHIMIZU1, Marina KISHIDA1, Ayako SATO1,
Takeshi TOMONAGA1（1Laboratory of Proteome Research National Institutes of Biomedical Innovation,
Health and Nutrition）

26G-ISMS39 Identification of WAC-224, a Novel Anticancer Quinolone as a Human Topoisomerase
II Inhibitor○ Tomonori YAMAGUCHI1, Kenji ITOH1, Taichi UESHIMA1, Rumiko SHIMABARA1,
Yohei KAWAKUBO1, Masayuki SATO1, Junpei YAMASHITA1, Tatsuya HIRANO1,
Akira YAZAKI1（1Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.）
26G-ISMS40 Lenvatinib Mesilate (LEN) Enhanced Antitumor Activity of a PD-1 Blockade Agent byPotentiating Th1 Immune Response○ Yu KATO1, Xingfeng BAO2, Shannon MACGRATH2, Kimiyo TABATA1, Yusaku HORI1,
Sho TACHINO1, Mark MATIJEVICI2, Yasuhiro FUNAHASHI1, Junji MATSUI1（1Eisai Co., Ltd.,
2

Tsukuba, Ibaraki, Japan, Eisai Inc. Andover, MA, USA）

26G-ISMS41 Identification of Blood-based Gene Expression Biomarkers for Major Depressive and
Bipolar Disorders○ Seiji NAKAMURA1, Hiroaki HORI2, Yohei ISHIZAWA1, Kenichi MATSUBARA1,
Ryo MATOBA1, Hiroshi KUNUGI2（1DNA Chip Research Inc., 2Department of Mental Disorder Research,
National Institute of Neuroscience, National Center of Neurology and Psychiatry）– 22 –

26G-ISMS42 Anti-Helicobacter Pylori Activity of a Novel Derivative of Intervenolin○ Tomokazu OHISHI1, Toru MASUDA1, Shun-ichi OHBA1, Chigusa HAYASHI2,
Hikaru ABE3, Masayuki IGARASHI2, Takumi WATANABE3 , Daniel Ken INAOKA4,
Kiyoshi KITA5, Masakatsu SHIBASAKI3, Manabu KAWADA1,6（1Institute of Microbial Chemistry
2(BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Institute of Microbial Chemistry (BIKAKEN),
3
Laboratory of Microbiology, Microbial Chemistry Research Foundation, Institute of Microbial Chemistry (BIKAKEN),
4
Laboratory of Synthetic Organic Chemistry, Microbial Chemistry Research Foundation, Center for International
5
Collaborative Research, Nagasaki University, School of Tropical Medicine and Global Health, Nagasaki University,
6
Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation）

26G-ISMS43 Discovery of Novel 5,6,7,8-tetrahydro[1,2,4]Triazolo[4,3-a ]Pyridine Derivatives asγ-secretase Modulators○ Takafumi TAKAI1, Tatsuki KOIKE1, Minoru NAKAMURA1, Yasutaka HOASHI1,
Yoshihide TOMATA1, Sachie MORIMOTO1, Yuichi KAJITA1, Toshiro YAMASHITA1,
Naohiro TAYA1, Tetsuya TSUKAMOTO1, Tomomichi WATANABE1, Koji MURAKAMI1,
Tomoko IGARI1, Makoto KAMATA1（1Takeda Pharmaceutical Company Limited）
26G-ISMS44 Regulatory Science for R&D Promotion of Innovative Pharmaceuticals*
Kazuhiko MORI1, Takao YAMORI2, ○ Toru KAWANISHI3, Takao INOUE4（1Ministry of Health,2

3

Labor and Welfare (MHLW), Pharmaceuticals and Medical Devices Agency (PMDA), National Institute of Health4
Sciences (NIHS), Japan Agency Medical Research and Development (AMED)）– 23 –

6 Abstracts
3rd International Symposium for Medicinal Sciences
Akira OTAKA

Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University

The objectives of this symposium are to encourage pharmaceutical company researchers who areinterested in drug discovery to participate in this annual meeting, and also to create an importantinternational platform for all those interested in the medicinal sciences. Since this symposium covers
the entire drug discovery field, we welcome participants from disciplines including pharmacology,
pharmacokinetics, and regulatory sciences.
One of the features of this symposium is a wide array of invited poster presentations. Since the program
will include high-caliber presentations from the Japanese and foreign pharmaceutical industries,
venture companies, and academia, young Japanese researchers who are interested in drug discovery
will have valuable opportunities for discussion with ﬁrst-class drug discovery researchers from aroundthe world.

Plenary Lecture 1

Tachibana Conference Hall 10:45−11:45

ISMS-PL01 Robot Scientists: Automating Drug Design
Ross D. KING
University of Manchester

A Robot Scientist is a physically implemented robotic system that applies techniques from
artificial intelligence to execute cycles of automated scientific experimentation. A Robot Scientist
can automatically execute cycles of: hypothesis formation, selection of efficient experiments todiscriminate between hypotheses, execution of experiments using laboratory automation equipment,
and analysis of results. The motivation for developing Robot Scientists is to better understand science,and to make scientiﬁc research more efﬁcient. The Robot Scientist ʻAdamʼ was the ﬁrst machine toautonomously discover novel scientific knowledge. Our new Robot Scientist, ʻEveʼ, is designed toautomate and integrate drug screening, hit conformation, and QSAR development. Its combination ofnovel automation with synthetic biology assays enables faster and cheaper drug design. Eveʼs focus
was originally on neglected tropical diseases, and Eve has discovered hits and leads against targets in
multiple parasites. We are now adapting Eve to work with and learn about human cancer cell lines.
There is currently a ʻreplication crisisʼ in biology, and many scientific results have been shown to
difﬁcult to replicate. We argue that the formalisation of protocols, combined with the automation ofexperiments, is the best way to replicate results.

– 24 –

Plenary Lecture 2

Tachibana Conference Hall 13:15−14:15

ISMS-PL02 Recent Advances in cryo-EM: Applications to Drug Discovery
Sriram SUBRAMANIAM
National Cancer Institute, NIH

Recent breakthroughs in the field of cryo-electron microcopy (cryo-EM) provide new prospects fordetermination of the structures of a variety of macromolecular assemblies and offer unprecedented
opportunities for drug discovery. The prospect that the determination of protein structures to atomic
resolution will no longer be limited by size, or by the need for crystallization represents a signiﬁcantand exciting horizon in structural biology. I will discuss the application of these methods to analyze
structures of a variety of biologically and medically relevant multi-protein complexes and membraneprotein assemblies, which have historically represented the most challenging frontier in structural
biology.
Selected publications:• Merk A., Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis M, Pragani R, Boxer M, Earl LA,
Milne JLS, Subramaniam S (2016) Breaking cryo-EM resolution barriers to facilitate drug discovery.
Cell, 165 1698-1707.
• Matthies D, Dalmas, O, Borgnia, MJ, Dominik, PK, Merk, A, Rao, P, Reddy, BG, Islam, S.,
Bartesaghi, A, Perozo, E, Subramaniam, S (2016) Cryo-EM Structures of the Magnesium Channel
CorA Reveal Symmetry Break Upon Gating. Cell, 164, 747-756.
• Banerjee, S, Bartesaghi, A, Merk, A, Rao, P. Bulfer, SL, Yan, Y, Green, N, Mroczkowski, B, Neitz,
RJ, Wipf, P, Falconieri, V, Deshaies, RJ, Milne, JLS, Huryn D, Arkin, M, Subramaniam S (2016) 2.3 Å
resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science, 351,871875.
• Meyerson JR, Chittori S, Merk A, Rao P, Han TH, Serpe, M, Mayer ML, Subramaniam S (2016)
Structural basis of kainate subtype glutamate receptor desensitization. Nature 537:567-571.
• Bartesaghi A, Merk A, Banerjee S, Matthies D, Wu X, Milne JLS, Subramaniam S (2015) 2.2 Å resolution
cryo-EM structure of β -galactosidase in complex with a cell-permeant inhibitor. Science 348:1147-1151.

– 25 –

Invited Poster Presentation
Short Presentation
Discussion

Tachibana Conference Hall 14:20−16:00
Meeting Room 4

Odd Number: 16:00−16:50 / Even Number: 16:50−17:40

26G-ISMS01 Unstructured Protein : A New Approach for Drug Discovery○ Takenao ODAGAMI1, Yoichiro HIROSE1, Yoshimasa IMAMURA1, Akira KATOH1,
Tadashi MISHINA1, Hiroyuki KOUJI1
1

Research & Development, PRISM BioLab Co., Ltd.

There are many successful examples in drug discovery of developing enzyme inhibitors and receptor
agonists/antagonists. However, attempts to develop modulators of protein/protein interaction havelargely been unsuccessful. This is especially true in developing modulators for transcription factors andfor doing so with small molecules.
Helix structures are prevalent and are often observed in intracellular protein/protein interactions.
PRISM has designed novel compounds based on helix structures and has developed small to middle
size molecules exhibiting strong activity in modulating critical intracellular protein/protein interaction.
In case of intracellular protein/protein interaction, unstructured (intrinsic disorder) region plays animportant role for their binding. The 50% of intracellular protein was estimated to have unstructured
region. Intrinsic disorder region is highly abundant among proteins associated with various humandiseases such as cancer, metabolic diseases, and cardiovascular diseases. However, systematic approachto target unstructured/structured protein/protein interaction has not been done in drug discovery
area, to the best of our knowledge. PRISM focused on the protein/protein interaction to explore drugcandidates. PRISM platform has resulted in a clinical-stage program based on targeting the CBP/betacatenin complex, as well as other preclinical drug development programs.
We would like to discuss here PRISMʼs platform technology that focused on unstructured/structured
protein/protein interaction to explore drug candidates.

26G-ISMS02 Development of Macrocyclic Peptide Targeting Ebola Glycoprotein○ Shiori UMEMOTO1, Junki MARUYAMA2, Ayato TAKADA2, Hiroaki SUGA1
1
2

Department of Chemistry, Graduate School of Science, The University of Tokyo,
Department of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University

Ebola virus (EBOV), a member of the ﬁlovirus family, causes severe hemorrhagic fevers with 50-90%
lethality. The EVOV glycoprotein (GP) is the sole virally expressed protein on the virion surface andis essential for attachment to the host cell and for membrane fusion. Hence, the EBOV GP is a critical
drug target for combatting ebola virus. However, a truncated GP variant (sGP) that is secreted from
infected cells may act as a decoy for drug candidate. As a result, high afﬁnity and speciﬁcity, such as an
antibody, is required for any drug targeting EBOV. We have previously developed a system, known as
the RaPID system, to evolve macrocyclic peptides that speciﬁcally and strongly bind to a target protein
and regulate function of the protein. The RaPID system combines ribosomal expression of a peptide
library including non-proteogenic amino acids with ribosomal display, allowing expression of vast
macrocyclic peptide libraries of up to trillions of macrocyclic peptides. In this poster, we introduce
our strategy to develop macrocyclic peptides that bind to EBOV GP, the most potent of which has adissociation constant of 6.3 nM, which is comparable of that of an antibody. The small size and potencyof these macrocyclic peptides will give a big advantage in choice of strategies for functionalization, as
well as easier handling and large scale production. They may therefore open up new strategy to combat
EBOV.

– 26 –

26G-ISMS03 Combinatorial Solid-Phase Synthesis and Biological Evaluation of

Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast
Morphology○ Hiroshi SATO1,2, Masahito YOSHIDA1, Hayato MURASE3, Hiroshi NAKAGAWA3,

Takayuki DOI1
1
3

Graduate School of Pharmaceutical Sciences, Tohoku University, 2Mitsubishi Tanabe Pharma Corporation,
Department of Applied Biological Chemistry, Chubu University

Cyclodepsipeptide destruxins were firstly isolated from Metarhizium anisopliae , and consist ofﬁve amino acids (β-Ala, L-MeAla, L-MeVal, L-Ile, and L-Pro) and an α-hydroxy acid derivative.1 In
particular, destruxin B (1) that possesses an isobutyl moiety as a side-chain on an α -hydroxy acidderivative, reversibly inhibits bone-resorbing activity of osteoclasts without affecting cell viability.2
Therefore, destruxins can be a promising candidate for developing novel anti-resorptive agents.
Because of structural and biological properties of 1, combinatorial synthesis and biological evaluationof cyclodepsipeptide destruxin B (1) were demonstrated.3 We designed 64-member analogues towardelucidation of structure-activity relationships, and the cyclization precursors were readily prepared bysolid-phase peptide synthesis using a split and pool method. After cleavage from the polymer-support,
macrolactonization utilizing MNBA-DMAPO in the solution phase was successfully performed inparallel to afford desired destruxin analogues in moderate to good yields. In this presentation, details ofcombinatorial synthesis and biological evaluation of the synthesized analogues will be discussed.
References
1. Païs, M.; Das, B. C.; Ferron, P. Phytochemistry 1981, 20 , 715 − 723.
2. Nakagawa, H.; Takami, M.; Udagawa, N.; Sawae, Y.; Suda, K.; Sasaki, T.; Takahashi, N.; Wachi, M.;
Nagai, K.; Woo, J. T. Bone 2003, 33 , 443 − 455.
3. Sato, H.; Yoshida, M.; Murase, H.; Nakagawa, H.; Doi, T. ACS Comb. Sci, 2016, 18 , 590-595.

26G-ISMS04 SAR Exploration of Selective Kinase Inhibitors based on the “Head-to-Tail”
Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds○ Satoru NOJI1, Noriyoshi SEKI1, Takaki MAEBA1, Takayuki SAKAI1, Eiichi WATANABE1,
Katsuya MAEDA1, Kyoko FUKUSHIMA1, Toru NOGUCHI1, Kazuya OGAWA1,
Yukiyo TOYONAGA1, Tamotsu NEGORO1, Hisashi KAWASAKI1, Makoto SHIOZAKI1
1

Central Pharmaceutical Research Institute, Japan Tobacco Inc.

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential speciﬁcity
is initially selected, followed by fine-tuning of the accompanying substituents on its core module.
A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all
the analogues in the series if a critical drawback is revealed. Thus, an early effort to prepare such a
potential risk by having a multiple series of compounds is rationalized, although there have been very
few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4
kinases and has recently drawn signiﬁcant attention as an emerging target for hepatitis C virus (HCV)
treatment. Inhibition of this host factor seems to provide a higher barrier to vial resistance as well asactivity against all existing HCV genotypes. In this presentation, a novel “Head-to-Tail” approach todiscover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct
core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

– 27 –

26G-ISMS05 Search for Anti-leukemic Drugs Targeting the Transcription Factor Runx1 by

INTENDD○ Masaaki SHIINA1, Shiho BABA1, Akiko UCHIYAMA1, Chikako OKADA1,

Takeshi TANAKA2, Ken IKEDA2, Shigetsugu KAWAKITA2, Takao MATSUZAKI2,
Hirotsugu KOMATSU2, Masato HOSODA2, Kazuhiro OGATA1
1

Yokohama City University, Graduate School of Medicine, 2Interprotein Corporation

Advance in the molecular targeted therapy has dramatically changed and improved a treatment of cancer. However, its
narrow target spectrum and acquired drug resistance in tumors remain to be solved. These problems partly stem fromthe limited variation of the targeted molecules; almost all have been protein kinases. To settle the problems, a promising
way is to develop drugs targeting proteins other than kinases. One of the potential targets is a transcription factor
because its mutation is known to be frequently involved in cancer development. However, transcription factors do nothave any enzymatic activity themselves, and thus the compounds necessarily target the molecular interactions involved,
which is quite challenging. This may explain why few drugs targeting transcription factors have been available as longas we know.
Our present research goal is to develop anti-leukemic drugs targeting a transcription factor, Runx1. Runx1 is known asa master regulator of the blood cell development, and various mutations of Runx1 gene have frequently been found inacute myeloblastic leukemia (AML) patients, leading to belief that Runx1 is an assured drug target for AML. Because
Runx1 binds target gene enhancers as a heterodimer with CBFβ to regulate transcription, the desired compounds arelikely to target the interactions of Runx1 with DNA or CBFβ .
We started our challenge with a unique type of in silico screening, INTENDD, which was developed by
INTEPROTEIN CORP. and stands for INTerproteinʼs Engine for New Drug Design. In this method, we eyeball a real
3D model produced by a 3D printer based on a protein structure to ﬁnd a molecular pocket for small compounds. Then,in silico screening is performed just for the candidate pockets. With INTENDD, we found and picked up 167 and142 compounds targeting Runx1-DNA and Runx1-CBFβ interactions, respectively. Then we evaluated the inhibitory
activity of the found compounds against DNA binding of Runx1 using surface plasmon resonance (SPR). We had
totally 49 positive compounds, 3 of which strongly inhibited DNA binding of Runx1 with IC50 below 1 µM. We haveveriﬁed that some of the positive compounds bind to Runx1 with the comparable afﬁnity (K D: 0.01-10 µM range).

26G-ISMS06 Evaluation of Novel Anti-Dengue Candidates Using In Silico and In Vitro

Approaches○ Yu-Shi TIAN1, Hitoshi MATSUDA2, Xinzhe LIU2, Norihito KAWASHITA2,3,

Tatsuya TAKAGI2,3
1

Graduate School of Information Science and Technology, Osaka University,
Graduate School of Pharmaceutical Sciences, Osaka University,
3
Graduate School of Information Science and Technology, Osaka University Research Institute forMicrobial Diseases
2

Dengue virus or DENV belongs to the family Flaviviridae and is mediated by mosquitoes. Most
patients appear in tropical and sub-tropical regions. Recently due to the climate change and theincrease of global travelers, the regions of DENV infections are no more limited and being enlarged.
The infections accompanying with hemorrhagic fever and/or shock syndrome became serious issues,
especially when patients were infected by a different serotype of DENV for the second time. Although
fruity studies on DENV have been carried out, so far no potent vaccine or antiviral drug has been
approved [1]. We reported SK-12 in 2013 as a novel active molecule which is considered to target theinteraction between non-structured viral proteins NS2B and NS3 [2]. In the current study, we look backinto NS3/NS2B protease, a famous target for anti-Dengue study. We used high-throughput screening
technique and In Silico studies to search for active candidates from compound libraries obtained from
Osaka University. We found several candidates showed anti-DENV activities. Subsequently, thesecompounds were carefully checked to compare with previously reported molecules. Based on the mostpromising candidate, a screening of novel commercial libraries were carried out to solve time consume.
We will present our results in the poster section and are looking afford for deep discussions.
[1] (One example) Lai H. et al . Bioorg. Med. Chem. 21 102–113 2013.
[2] Pambudi S. et al . Biochem. Biophys. Res. Commun. 440 (3) 393-398 2013.
– 28 –

26G-ISMS07 Development and Construction of an Original Compound Library for CNS

Drug Discovery: Combining Computational and Wet Data to Enhance CNS
Drug-likeness○ Daiju HASEGAWA1
1

Medicinal Chemistry, Neurology Tsukuba Research Department, Discovery, Medicine Creation,
Neurology Business Group, Eisai Co., Lid.

High quality HTS hits are important for drug discovery programs to accelerate medchem campaign toclinical candidate and improve the overall success rate in the drug development. To provide such highquality HTS hits, sophisticatedly designed compound libraries play an important role in HTS strategy.
In addition, a compound library with enhanced CNS drug-likeness (good brain penetrability and goodoral availability) should improve the productivity of drug discovery programs in the neuroscience area.
Against this background, we have been constructing a CNS-focused compound library by:• Innovative design to improve the probability of the compounds reaching the CNS.
• Extensive in vitro , in vivo and physicochemical characterization of library members to eliminate
structures with inherent liabilities.
• Newly-designed compounds based on structurally novel scaffolds.
In this poster, we describe our strategy for constructing a CNS-focused compound library utilizing the
combination of a computational scoring system and in vitro/in vivo DMPK data. In addition, we also
describe how we gathered our original scaffold collection to emphasize structural novelty in the library.

26G-ISMS08 Structure-based Design, Synthesis, and Biological Evaluation of Imidazo[1,2-b ]Pyridazine- based p38 MAP Kinase Inhibitors○ Akira KAIEDA1, Masashi TAKAHASHI1, Takafumi TAKAI1, Masayuki GOTO1,

Takahiro MIYAZAKI1, Yuri HORI1, Satoko UNNO1, Tomohiro KAWAMOTO1, Toshimasa
TANAKA1, Sachiko ITONO1, Terufumi TAKAGI1, Teruki HAMADA1, Mikio SHIRASAKI1,
Kengo OKADA1, Gyorgy SNELL2, Ken BRAGSTAD2, Bi-Ching SANG2, Osamu
UCHIKAWA1, Seiji MIWATASHI1
1

Takeda Pharmaceutical Company Limited, 2Takeda California, Inc.

We have identiﬁed a novel series of potent p38 MAP kinase inhibitors through structure-based design
strategy. In the X-ray co-crystal structure of p38 MAP kinase with TAK-715 (1), Phe169 adopts two
conformations that one interacts with 1 and the other shows no interaction with 1. Our structure-based
design strategy is that these two conformations converge on one conformation by enhancement of theprotein-ligand hydrophobic interaction. Scaffold transformation was conducted to enhance the proteinligand hydrophobic interaction to resulting in the identiﬁcation of imidazo[1,2-b ]pyridazine derivatives
as a lead series of potent p38 MAP kinase inhibitors, followed by investigation of structure and DMPK
profile relationship. We provide a rational design, synthesis, SAR studies, and biological studies ofimidazo[1,2-b ]pyridazine derivatives.

– 29 –

26G-ISMS09 Flow Chemistry: New Horizons in Chemical Space for the Creation of Next

Generation Libraries

Daniel BLANCO-ANIA3, Sagar Ashok GAWADE1, Luuk MAARTENSE1,
Roel VERLEIJSDONK1, Remco MERKX2, Huib OVAA2, Floris RUTJES1,
Marjon BOLSTER3, Luc ZWINKELS3, Joeri SCHEIDT3, Pauline van MEURS3,
Jorg BENNINGSHOF3, ○ Norimasa MORITA3
1

Radboud University, 2Leiden UMC (Former NKI), 3MercachemAs a member of the European Lead Factory (ELF), Mercachem is responsible for generation,
validation and production of libraries consisting of ~10,000 compounds from ~20 scaffolds per year.
This poster presents two examples where continuous flow chemistry facilitated the synthesis ofscaffolds (and their corresponding libraries) with limited accessibility in batch processes. First, a 700
membered imidazolidinone library was smoothly prepared by the generation and subsequent reductionof an unstable and explosive azide keyintermediate in ﬂow. Secondly, photochemistry in ﬂow enabled
the construction of two conformationally restricted three-dimensional aminoketone scaffolds at large
scale in unprecedented efﬁciency.

26G-ISMS10 Transition Metal-Free, Tryptophan-Selective Bioconjugation of Proteins○ Kounosuke OISAKI1, Yohei SEKI1, Takashi ISHIYAMA1, Daisuke SASAKI1,2,
Junpei ABE1, Yohei SOHMA1,2, Motomu KANAI1,2
1
2

Graduate School of Pharmaceutical Sciences, The University of Tokyo,
JST, ERATO Kanai Life Science Catalysis ProjectChemical modiﬁcations of native proteins can facilitate production of supernatural protein functions
that are not easily accessible by complementary methods relying on genetic manipulations. Even
though precise control over the chemo-, site, and modiﬁcation-number selectivity in protein chemical
conjugates with maintained structural integrity and homogeneity is highly important, it still represents
a major challenge. The available toolbox of native protein conjugations does not contain satisfactory
solutions to this challenge at present. In many cases, the conjugation sites are located at the side chainsof lysine and cysteine residues. Despite recent improvements, these methods often afford unsatisfactory
levels of selectivity with disintegrated higher-order structures.
We report a transition metal-free method for tryptophan-selective bioconjugation of proteins that isbased on an organoradical and operates under ambient conditions. This method exhibits low levels ofcross-reactivity and leaves higher-order structures of the protein and various functional groups therein
unaffected. The strategy to target less abundant amino acids contributes to the formation of structurally
homogeneous conjugates, which may even be suitable for protein crystallography. The absence of toxic
metals and biochemically incompatible conditions may thus easily ﬁnd therapeutic applications.

– 30 –

26G-ISMS11 Total Synthesis of Halichondrin A and C○ Akihiko YAMAMOTO1, Atsushi UEDA1, Paul BRÉMOND1, Paolo S. TISENI1,
Daisuke KATO1, Yoshito KISHI1
1

Department of Chemistry and Chemical Biology, Harvard University

The first total sythesis of Halichondrin A and C was achieved by utilizing multiple Cr-mediatedcoupling to form a new C-C bond*. Halichondrins A/C are C12- and C13-di-hydroxylated / C12hydroxylated form of Halichondrin B, whose right-half substructure led to the antitumor drug Eribulin(Figure 1 ). The syntheses are highlighted by the construction of C8-C14 polycyclic ketal for both A and
C (Figure 2 ).

* J. Am. Chem.Soc. 2014, 136 , 5171-5176, J. Am. Chem.Soc. 2012, 134 , 893−896

26G-ISMS12 Parallel Fluorescent Probe Synthesis Based on the Large-scale Preparation of

BODIPY FL Propionic Acid

○ Taisuke KATOH1, Masato YOSHIKAWA1, Takeshi YAMAMOTO1, Ryosuke ARAI1,

Noriyuki NII1, Yoshihide TOMATA1, Shinkichi SUZUKI1, Ryoukichi KOYAMA1,
Nobuyuki NEGORO1, Takatoshi YOGO1
1

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd

We describe a methodology for quick development of ﬂuorescent probes with the desired potency
for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent
Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but is
an expensive reagent, which hinders its use in parallel synthesis. Optimization of a synthetic scheme
enabled us to obtain 50 g of 1 in one batch. With this large quantity of 1 in hand, we performed
Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of
the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50 = 80 nM),demonstrating the usefulness of Parallel-FPS.

– 31 –

26G-ISMS13 Improvement in Pharmacokinetics and In Vivo Activity of Somatostatin by

Chemical Glycosylation○ Hirofumi OCHIAI1, Jun IGARASHI1, Hayato SAIJO1, Takahiro YAMAMOTO1,

Yuji NISHIUCHI1, Akio KANATANI1, Taiji SHIMODA1
1

GlyTech, Inc.

Somatostatin is naturally occurring peptide hormone that inhibits the secretion of several hormones
through the binding to five distinct receptor subtypes. Despite the wide variety of its activity,
therapeutic indications of native somatostatin are limited due to its short plasma half-life. In the present
study, we synthesized glycosylated somatostatin analogs by chemically attaching one to four complex
type sialyloligosaccharide chain(s) to the somatostatin molecule. The plasma half-life was extended
by approximately 10-fold by the attachment of a single glycan, and the half-lives were prolonged byincreasing the number of attached glycans. A single glycan-attached somatostatin maintained a highaffinity to all receptor subtypes as in the case of native somatostatin. Furthermore, the glycosylated
somatostatin demonstrated an efficient inhibition of growth hormone release in rats. These results
indicate that glycosylated somatostatin analogs could be a potent therapeutic drug candidate for several
diseases where somatostatin receptor subtypes are closely involved.

26G-ISMS14 Development of an Oxidative Mizoroki-Heck Reaction for Late-stage C-HFunctionalization of Complex Molecules and Application to Pharmaceutical
Studies○ Kenji WATANABE1, Amrita DAS1, Takumi KIMIJIMA1, Tomohiro YAMASHITA1,

Kazuhide INOUE1, Makoto TSUDA1, Takashi OHSHIMA1
1

Graduate School of Pharmaceutical Sciences, Kyushu University

Duloxetine, a serotonin and noradrenaline reuptake inhibitor, was recently found to inhibit P2X4
receptors in microglial cells, and reduce nerve injury-induced allodynia in rats.1) Therefore, chemical
modiﬁcation of duloxetine may lead to the development of a potent drug for treating neuropathic pain.
To synthesize a variety of duloxetine derivatives in a highly efficient way, we adopted a late-stage
C–H functionalization strategy. Our initial trials using conventional C–H activation methods, however,resulted in the elimination of the naphtoxy group of duloxetine by due to severe reaction conditions.
Therefore, we focused on the development of a new C–H activation reaction proceeding under neutral
and mild condition, and ﬁnally we achieved a selective oleﬁnation of the thienyl group of duloxetine
through catalytic oxidative Mizoroki-Heck reaction using molecular oxygen as the terminal oxidant.2)
Under the optimized reaction conditions, various alkenyl groups were introduced into duloxetine in ahighly regioselective manner. The obtained products were further transformed to various duloxetine
derivatives, some of which showed improved biologic activity. We further studied fundamental
reactivity of the reaction against various electron-rich arenes and hetero-arenes, and applied to latestage functionalizations of several natural and medicinal compounds to demonstrate the utility of thereaction for the construction of chemical libraries of complex molecules.
1) Yamashita, T.; Yamamoto, S.; Zhang, J.; Kometani, M.; Tomiyama, D.; Kohno, K.; Tozaki-Saitoh, H.;
Inoue, K.; Tsuda, M. PLOS ONE 2016, 11 (10): e0165189. doi:10.1371/ journal.pone.0165189.
2) Manuscript in preparation.
– 32 –

26G-ISMS15 Functional Characterization of Acetylcholine Receptors in Human

Hippocampus-Derived Neurons○ Kazuyuki FUKUSHIMA1, Kazuto YAMAZAKI2, Norimasa MIYAMOTO3,

Kohei SAWADA3
1

Neurology Tsukuba Research Department, Discovery, Medicine Creation, Neurology Business Group,
Eisai Co., Ltd., 2Technology Cross Point Laboratory, hhc Data Creation Center, Eisai Co., Ltd.,
3
Global CV Assessment, BA CFU, Medicine Development Center, Eisai Co., Ltd.

Utilizing human cell models mimicking physiologically- and/or disease-relevant conditions is a
key strategy to improve success rates in drug development. To apply the strategy to the CNS drug
development, it is essential to obtain functional human neurons. As a tool to generate functional
human neurons, we utilized human hippocampus-derived neural stem/progenitor cells (HIP-009 cells).
We previously demonstrated that HIP-009 cells can differentiate into neurons expressing glutamate
receptors functionally, and that they were applicable to assessment system of drug candidates forglutamate receptor-related neurological disorders including Alzheimerʼs disease (AD). In addition to
glutamate receptors, acetylcholine receptors (AChRs) are another target group for AD therapeutics.
Here, we examined the potential to apply HIP-009 neurons to functional assessment of drug candidates
targeting AChRs. qRT-PCR analysis revealed that expression of nicotinic (nAChR) and muscarinic
acetylcholine receptor (mAChR)-related genes was upregulated after four-week differentiation. Ca2+
ﬂux assays of HIP-009 neurons demonstrated that intracellular Ca2+ signals were increased by nicotine
and muscarine, indicating that HIP-009 neurons expressed nAChRs and mAChRs functionally. We also
pharmacologically investigated expression of each subtype by using subtype-selective compounds,
and identiﬁed functional expression of α7 and α4β2 nAChRs, as well as M1 and M3 mAChRs. These
results suggest that HIP-009 neurons are applicable to functional evaluation of drug candidates acting
on AChRs for AD drug development.

26G-ISMS16 Analgesic Effect of Novel 11 β -HSD1 Inhibitor ASP3662 and its Mechanism of

Action in a Spinal Nerve Ligation Model of Neuropathic Pain

○ Tetsuo KISO1, Toshihiro SEKIZAWA1, Mina TSUKAMOTO1, Junko YARIMIZU1,

Shuichiro KAKIMOTO1
1

Drug Discovery Research, Astellas Pharma Inc.

Glucocorticoids exert their effects via glucocorticoid receptors (GRs), and the central GR is reportedly involved in
the mechanism of neuropathic pain. 11β -hydroxysteroid dehydrogenase 1 (11β -HSD1) is involved in the conversionof inactive glucocorticoids to active glucocorticoids and is expressed not only in peripheral tissues but also in thecentral nervous system (CNS), such as brain and spinal cord. However, what role̶if any̶11β -HSD1 plays in paintransmission remains unclear. ASP3662 is a novel 11β -HSD1 inhibitor discovered through our research. Here, weinvestigated the analgesic effect and mechanism of ASP3662 in a spinal nerve ligation (SNL) model of neuropathic
pain in rats. In SNL model rats, the left L5 and L6 spinal nerves were tightly ligated with silk thread. For intrathecal
administration, the catheter was inserted between the L5 and L6 vertebrae. In the microdialysis experiment, the spinal
cord dialysis probe was passed transversely through the dorsal spinal cord via bilateral holes made through vertebra L1.
The mechanical threshold was determined by the von Frey hair test. ASP3662 concentrations in plasma and brain were
determined via liquid chromatography-tandem mass spectrometry. One week after spinal nerve ligation, mechanicalthresholds of the operated-side hindpaw were clearly lower than those in the sham group (mechanical allodynia). Single
oral doses of ASP3662 signiﬁcantly ameliorated mechanical allodynia, with an ED50 value of 0.087 mg/kg at 2 h afteradministration. Intrathecally administered ASP3662 also alleviated mechanical allodynia. A pharmacokinetics study
using SNL model rats revealed CNS penetration by this compound. In a microdialysis experiment, intraperitoneallyadministered corticosterone, the active glucocorticoid in rodents, signiﬁcantly increased spinal glutamate concentrations
in normal rats. Intraperitoneally administered 11-dehydrocorticosterone (11-DHC), the inactive glucocorticoid inrodents, significantly increased spinal glutamate concentrations in an SNL model but not in normal rats. ASP3662
signiﬁcantly inhibited this 11-DHC-induced increase in glutamate. ASP3662 is a novel, CNS-penetrable 11β -HSD1
inhibitor which alleviates mechanical allodynia in SNL rats. These results suggest that this compound is a promising
candidate for use in treating neuropathic pain. One site of action of ASP3662 is the spinal cord. This compound may
block glucocorticoid-induced increases in spinal glutamate concentration in SNL model rats by inhibiting conversion of
inactive glucocorticoids into active ones.

– 33 –

26G-ISMS17 Atomic-Scale Investigation on Acetaminophen Crystals with Stable and Metastable

Phases by Frequency Modulation Atomic Force Microscopy in Aqueous Solution○ Naritaka KOBAYASHI1, Kazuki OKANO2, Yoichiro MORI3, Shun FUKUKITA3,

Mihoko MARUYAMA4, Hiroaki ADACHI3,5, Kazufumi TAKANO4,5, Satoshi MURAKAMI5,6,
Hiroyoshi MATSUMURA5,7, Tsuyoshi INOUE3,5, Masashi YOSHIMURA5,8, Yusuke MORI3,5,
Seiichiro NAKABAYASHI1, Hiroshi YOSHIKAWA1,3
1

Graduate School of Science and Engineering, Saitama University, 2Faculty of Science, Saitama University,
Graduate School of Engineering, Osaka University, 4Graduate School of Life and Environmental Sciences,
Kyoto Prefectural University, 5SOSHO, Inc., 6Graduate School of Bioscience and Biotechnology, Tokyo
Institute of Technology, 7College of Life Science, Ritsumeikan University, 8Institute of Laser Engineering,Osaka University
3

Selective crystallization methods of metastable phase of medicinal organic compounds have been
being developed to improve bioavailability in pharmaceutical application. These crystals are often
grown from liquid phase. Therefore, it is quite useful for acceleration of the development to understandatomic-scale processes at crystal-solution interfaces.
Frequency modulation atomic force microscopy (FM-AFM) is a powerful tool that can image
surface structures with atomic resolution in liquid. FM-AFM has recently enabled us to visualize
water molecules localized at solid-liquid interfaces by measuring 3D force distribution. The water
distribution is called as hydration structure, which plays important roles in crystal growth. We havebeen investigating atomic-scale surface processes of acetaminophen (paracetamol) crystals with stable(Form I, monoclinic) and metastable (Form II, orthorhombic) phases by home-built atomic-resolution
FM-AFM.
We succeeded in obtaining atomic resolution images of Form I and II by imaging during theirdissolution in nearly-saturated solutions. This is the ﬁrst demonstration of atomic resolution imaging ofsoluble meta- stable crystal. We also revealed subnanoscale hydration structures formed on the surfacesof Form I and II.

26G-ISMS18 Anti-inﬂammatory Flavan-dihydrochalcones with Unprecedented Carbon

Skeletons from Daemonorops Draco○ Ping-Chung KUO1, Hsin-Yi HUNG1, Tsong-Long HWANG2, Tian-Shung WU1
1School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung
University, Tainan, 2 Graduate Institute of Natural Products, College of Medicine, Chang Gung University

Four flavan-dihydrochalcones with unprecedented carbon skeletons, dragonins A-D (1-4) werecharacterized from the traditional Chinese medicine Sanguis Draconis. The structures of 1-4 were
elucidated by spectroscopic and spectrometric analyses. Compounds 1 and 2 exhibited significant
inhibition of fMLP/CB induced superoxide anion generation and elastase release. These puriﬁed ﬂavandihydrochalcones are potentially new leads for anti-inﬂammatory drug development.

– 34 –

26G-ISMS19 Development of a Fully Automated HPLC System (ASAPrepTM) Designed forMultiple Compound Puriﬁcations○ Chie KUSHIBE1, Katsuhiko MIWA1, Hidetoshi TERADA2, Yuji KATSUYAMA2
1

Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical
Company Limited, 2Life Science Business Department, Analytical & Measurement Instruments Division,
Shimadzu Corporation

An automated decision-making process enabling seamless transitioning from analytical to preparative
scale has been developed in collaboration with Shimadzu to improve puriﬁcation process by ReversedPhase High-Performance Liquid Chromatography-Mass Spectrometry (RP-HPLC-MS). Our method
scouting protocol is based on database mining of alternative conditions to identify proﬁtable separation
conditions, like acidic or neutral mobile phases. An intelligent data processing software, in particular“MS spectral purity” significantly improves accuracy of decision-making. This innovative system,

named “ASAPrepTM (Automated Scale-up from Analytical to Preparative)” has just been released
globally in August 2014 from Shimadzu.
In this poster presentation, we will show the advantages of this system, while highlighting the noveltyof the puriﬁcation procedures compared to the existing technology.

26G-ISMS20 Discovery of a Novel PDE10A Inhibitor as Highly Effective for Schizophrenia○ Yoichi KADOH1, Takehiko MATSUMURA1, Yoshihito TANAKA1, Mitsuya HONGU1,
Haruko MIYOSHI1, Mayumi KIMURA1, Kei TAKEDOMI1, Kenji OMORI1, Jun KOTERA1,Takashi SASAKI1, Kiichi TANAKA1, Keiko MIWA1, Tamaki KOBAYASHI1,
Hiroyuki TANIGUCHI1, Taketoshi ISHII1, Yumi WATANABE1, Haruna ITODA1,
Rikiya OHASHI1, Kouki KOJIMA1, Masaya FUKUDA1, Saori SATO1, Itsuko NAKAMURA1,
Toshiaki SAKAMOTO1, Toshiyuki HIMIYAMA1, Masataka HIKOTA1, Eiji KAWANISHI1
1

Mitsubishi Tanabe Pharma Corporation

Phosphodiesterase10A (PDE10A), a dual hydrolase of cAMP and cGMP, is highly expressed in striatal
medium spiny neurons (MSN). Inhibition of PDE10A modulates the activity of MSN via the regulationof cAMP. Therefore PDE10A inhibitor is expected as a therapeutic method for schizophrenia. We
transformed Avanafil 1 (PDE5 inhibitor) derivatives, and discovered compound 2 that had weak
inhibitory activity against PDE10A. More conversion of compound 2 improved the metabolic stability
and brain penetration, and dimethylaminoquinoxaline substituted compound 3 that attenuatedconditioned avoidance responses (CAR) in rats was produced. We performed in-depth optimization,and successfully obtained stilbene compound 4. The compound was substituted with 3-methyl-7-ﬂuoro
quinoxaline substituents, and reduced genotoxicity and CYP inhibition.

– 35 –

26G-ISMS21 Nucleic Acid Drugs Large Scale Manufacturing and Speciﬁcation

Assay– Equivalency Solid Phase versus AJIPHASE® and Oligonucleotide
Sequences Conﬁrmation for IND and NDA○ Satoshi INOUE1, Hirokazu NANKAI1, Emi SAITO1, Hideaki SATO1, Kazuhiko YUYAMA1
1

GeneDesign, Inc.

Oligonucleotides which constitutes nucleic acid drug, are provided by chemical synthesis. We
already have several track records of the GMP production of some nucleic acid drugs. All thesebatches were synthesized by solid phase synthesis which is well established organic chemistry but it islimited for scalability and cost effectivity. To overcome this issue, we have been co-developed liquid
phase synthetic methodology of oligonucleotides called AJIPHASE® originated by AJINOMOTO.
Comparison data between solid phase and AJIPHASE® showed that two methods are equivalent for
impurity proﬁle and purity. This result shows one of breakthrough of cost effective nucleic acid drug
development. We believe nucleic acid drugs development is accelerated by AJIPHASE®.
On the other hand, in the analysis of nucleic acid drugs for specification, sequence confirmation
examination is critical test of identiﬁcation. We show example of sequence conﬁrmation examination
using MS different methodologies.
We can cope to IND and NDA by above-mentioned production technology and analysis technique.

26G-ISMS22 Amycolamicin, a Novel Antibiotic as a Promising Candidate for

Clostridium Difﬁcile Infection: Antibacterial Activity, Mode of Action, andIn Vivo Efﬁcacy○ Yoshimasa ISHIZAKI1, Kazushige SASAKI1, Hideki HASHIZUME1, Chigusa HAYASHI1,

Kunio INOUE1, Hayamitsu ADACHI1, Yoshiaki TAKAHASHI1, Masayuki IGARASHI1,
Yoshio NISHIMURA1, Yuzuru AKAMATSU1, Akio NOMOTO1, Masakatsu SHIBASAKI1
1

Institute of Microbial Chemistry (BIKAKEN)

A novel antibiotic amycolamicin (AM) discovered from the culture broth of Amycolatopsis sp. MK575fF5 was originally isolated as a drug which showed strong antibacterial activities against Gram-positivebacteria such as MRSA, VRE and PRSP. Mode of action study revealed that AM inhibited bacterial
DNA gyrase with IC50 of 24.4 ng/ml, without cross-resistance to other inhibitors of DNA gyrase such asquinolones and aminocoumarins. By contrast, AM did not inhibit human DNA topoisomerase II.
Additionally, AM showed particularly strong antibacterial activity against C. difficile grownanaerobically. The MIC90s (n=45) of AM, vancomycin, and fidaxomicin were 0.25, 1.0, 0.25 µg/ml,
respectively. AM also showed strong antibacterial activity against 13 species of Clostridiales , some
Bacteroidales and Enterococcus faecalis/faecium , whereas showed moderate or weak antibacterial
activity against other enteric bacteria including Bifidobacteriales , Lactobacillales and some
Bacteroidales . In a therapeutic experiment using for antibiotic- associated pseudomembranous colitis
caused by C. difficile ATCC 43255 in hamsters, AM showed an equivalent therapeutic efficacy toﬁdaxomicin at 6, 20, and 60 mg/kg/day by oral administration (n=7).
In conclusion, AM showed to possess strong activity against C. difficile with novel mechanism ofaction. The efﬁcacy in hamster model for pseudomembranous colitis warrants further evaluation of AM.
– 36 –

26G-ISMS23 Identiﬁcation and Optimization of a Novel Series of Tetrahydroisoquinoline

Derivatives as an Orally Active MGAT2 Inhibitor○ Tsuyoshi BUSUJIMA1, Hiroaki TANAKA2, Eiji MUNETOMO3, Kiyokazu KITANO3,

Masako SAITO3
1
3

Pharamceutical Science Laboratories, 2Chemistry Laboratories,
Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.

MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug
treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity
relationship (SAR) study of 2,3-dihydro-1H -isoindole-5-sulfonamide derivatives which was derived
from a hit compound identiﬁed by our high throughput screening campaign. In this study, we identiﬁed
an orally available MGAT2 inhibitor through optimization in terms of solubility. This compound
exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and an in vivo efﬁcacy atan oral dose of 100 mg/kg in a mouse oral lipid tolerance test.
Further optimization of a novel series of 1,2,3,4-tetrahydroisoquinoline-6-sulfonamide derivatives toimprove the intrinsic potency culminated in the identiﬁcation of TP0455353, 2-[2-(4-tert -butylphenyl)
ethyl]-N -[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroiso-quinoline-6-sulfonamide,
which was the most potent MGAT2 inhibitor among this series with an IC50 value of 28 nM. Oraladministration of TP0455353 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in signiﬁcant
suppression of triglyceride synthesis.

26G-ISMS24 Discovery of Novel Fluoroquinolone Antibiotics WFQ-101 and

Its Optimization Study○ Tatsuya HIRANO1, Tomohiko KINOSHITA1, Daichi KAZAMORI1, Satoshi INOUE1,

Kouji NISHIMURA1, Asuka SAKURAI1, Ayuka SASAKI1, Yasuhiro KURAMOTO1,
Hirotaka AMANO1, Akira YAZAKI1
1

Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.

As the difﬁcult-to-treat infections caused by multidrug-resistant bacteria have spread, it is an urgent
need to develop novel antibiotics for the treatment of them. Therefore, we started the research todiscover novel antibiotics with potent antibacterial activities, especially against Gram-negative resistantpathogens.
Recently, we evaluated the minimum inhibitory concentration (MIC) of our quinolone library for

P. aeruginosa with or without the efﬂux pump inhibitor PAβN. We found that the MICs of a certain
type of compounds such as WFQ-101, having 2-hydroxymethylphenyl group at 1-position, wereless changed by the presence of PAβN, indicating the possibility to overcome the drug resistance bybacterial efﬂux system. We selected WFQ-101 as a lead compound and have continued its structural
optimization. For example, an introduction of 5-methyl group drastically increased the activity,
whereas the modiﬁcation of 7-substituent, such as the increases of lipophilicity and/or bulkiness, was
not tolerated for the activity against Gram-negative pathogens. In this presentation, we will describe theresults of our optimization study, demonstrating the Structure-Activity Relationship.

– 37 –

26G-ISMS25 Anti-CTLA-4 Antibody scFv Producing Recombinant Biﬁdobacterium

Secretes CTLA-4 Blocker Speciﬁcally Inside Hypoxic Tumor and Suppresses
Tumor Growth in Syngeneic Mice Model○ Shiro KATAOKA1, Koichiro SHIOYA1, Li WANG1, Tomio MATSUMURA1,

Hitomi SHIMIZU1, Yasuyoshi KANARI1, Yuji SEKI1, Yuko SHIMATANI1,
Minoru FUJIMORI2, Shunʼichiro TANIGUCHI3
1

Anaeropharma Science, Inc., 19-8, Nihonbashi Kabuto-cho, Chuo-ku, Tokyo 103-0026, Japan,
Department of Breast Surgery, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan,
3
Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine
2Anti-PD-1 antibody and anti-CTLA-4 antibody showed notable efficacy and the combination
complimentarily enhanced antitumor beneﬁt. Nevertheless, either single-agent therapy or combination
therapy is facing immune-related adverse events (irAEs), which are major cause of treatment
discontinuation. Non-speciﬁc systemic activation of normal immune system by the therapy is one ofmajor reasons to cause the problems. Approaches to increase the delivery of checkpoint blockers totumor site may minimize the irAEs and improve the response rate in patients.
In an aim to improve efﬁciency of anti-cancer drug delivery, we have been developing in situ Delivery
and Production System (i -DPS) by modifying a non-pathogenic anaerobic bacterium, Biﬁdobacterium ,which localizes and proliferates only in the hypoxic environment like solid tumors after I.V.
administration and also produces anticancer proteins, enzymes or other pharmacologically active
molecules selectively at the tumor site. Here we present anti-CTLA-4 antibody scFv producing i- DPS
in cancer immunotherapy, which could be speciﬁcally delivered to and ampliﬁed only at the hypoxic
sites of solid tumors.

26G-ISMS26 Structural Basis for Activation of Neisseria Meningitides Elongation Factor

P with Arginine-32 Rhamnosylation by EarP
○ Toru SENGOKU1
1

RIKEN Structural Biology Laboratory

Protein glycosylation is a universal post-translational modiﬁcation regulating many cellular processes.
The only known protein arginine rhamnosyltransferase, EarP, specifically rhamnosylates Arg32
of elongation factor P (EF-P). We report a crystallographic study of Neisseria meningitidis EarP.
EarP binds the entire beta-sheet structure of domain I of EF-P, forming numerous interactions thatspeciﬁcally recognize its conserved sequences. This recognition mechanism, which is both structureand sequence-specific, sharply contrasts with those of other known glycosyltransferases that accept
substrates with different sizes and/or sequences. A molecular dynamics simulation suggested that therhamnose moiety should change its conformation during the reaction. These insights should facilitate
the development of new EarP inhibitors that target only EarP-containing pathogenic bacteria.

– 38 –

26G-ISMS27 Design, Synthesis and Biological Evaluation of a Novel Series ofPeripheral-selective Noradrenaline Reuptake Inhibitor, Part I -Lead Series
Discovery and Biological Concept Validation○ Ikuo FUJIMORI1, Tomoya YUKAWA1, Taku KAMEI1, Yoshihisa NAKADA1,

Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Maiko TAKIGUCHI1,
Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1, Teruki HAMADA1, Tomoko
IGARI1, Teruaki OKUDA1, Satoshi YAMAMOTO1, Tetsuya TSUKAMOTO1, Yuji ISHICHI1,
Hiroyuki UENO1
1

Takeda Pharmaceutical Company Limited

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients withstress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study
with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous
systems and the contribution of each site to efficacy has not been clarified. This poster describes
the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate thecontribution of the peripheral site to increasing urethral resistance in rats. An acetamide derivative
which showed high peripheral NET selectivity in rats increased urethral resistance in a dose-dependent
manner and exhibited a maximal effect on par with esreboxetine. These results indicate that theurethral resistance-increasing effects of NRI in rats are fully achieved by the peripheral selective NET
inhibition.

26G-ISMS28 Design, Synthesis and Biological Evaluation of a Novel Series ofPeripheral-selective Noradrenaline Reuptake Inhibitor, Part II -Lead
Optimization with Avoiding P-gp Substrate and Genetic Polymorphism○ Tomoya YUKAWA1, Ikuo FUJIMORI1, Taku KAMEI1, Yoshihisa NAKADA1,

Nobuki SAKAUCHI1, Masami YAMADA1, Yusuke OHBA1, Hiroyuki UENO1,
Maiko TAKIGUCHI1, Masako KUNO1, Izumi KAMO1, Hideyuki NAKAGAWA1,
Yasushi FUJIOKA1, Tomoko IGARI1, Yuji ISHICHI1, Tetsuya TSUKAMOTO1
1

Takeda Pharmaceutical Company Limited

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatmentof stress urinary incontinence to overcome adverse effects associated with central action. Herein, we
describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake
inhibitors to avert the risk of P-gp-mediated DDI at the blood–brain barrier. We observed that stericshielding of the HBA and HBD reduced the multidrug resistance protein 1 (MDR1) efflux ratio;
however, the resulting compound was mainly metabolized by CYP2D6 and CYP2C19 in the invitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism.
Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led tocompound, which was mainly metabolized by CYP3A4. To our knowledge, this study represents theﬁrst report of the effect of deuterium replacement for a major metabolic enzyme.

– 39 –

26G-ISMS29 Ex Vivo Gene-manipulated Mature Adipocytes: Novel Gene Therapy Medicine

for Sustained Protein Replacement Therapy of Variety of Intractable Diseases○ Masayuki KURODA1, Hideaki BUJO2, Koutaro YOKOTE3, Yasushi SAITO4, Masayuki ASO5
1

Center for Advanced Medicine, Chiba University, 2Department of Clinical Laboratory Medicine, Toho
University Medical Center Sakura Hospital, 3Department of Clinical Cell Biology and Medicine, Graduate
School of Medicine, Chiba University, 4Superintendent of the hospital bureau, City Hall of Chiba,
5CellGenTech, Inc.

Gene therapy-based protein replacement is one of absolute needs for treatment of inherited diseases.
Based on much experiences of clinical transplantation therapy in cosmetic and reconstructive surgery,adipose tissue is now recognized as a source of proliferative cells for cell-based therapy. We havedeveloped manipulation procedure of mature adipocytes through ceiling culture with subsequent
retroviral/lentiviral gene transduction. The propagated cells, designated as ceiling culture-derived
proliferative adipocytes (ccdPAs), provide efﬁcient gene transduction efﬁciency with stable secretion of
the transduced-gene products. GMP production procedure, by which the gene-transduced ccdPAs could
be expanded up to nearly 1012 cells from 1 g of fat tissue for three weeks after fat tissue preparation,
has been developed. The platform technology has been applied for ex vivo gene therapy of familial
lecithin:cholesterol acyltransferase (LCAT) deﬁciency. Clinical ﬁrst in human study for treatment offamilial LCAT deﬁciency has been approved by Ministry of Health, Labour and Welfare, followed byinitiation of patient enrollment in Japan. We further continue our research and development to obtainapproval as gene therapy medicine. Thus, ccdPAs would provide an excellent platform for developing
a protein replacement therapy not only for LCAT deficiency but also variety of intractable diseases
including hemophilia and lysosomal storage diseases.

26G-ISMS30 Application of Novel Highly Immunodeﬁcient Mice for Patient Derived Xenograft(PDX) Model and Evaluation of Anticancer Therapy○ Seiji OKADA1, Kulthida VAETEEWOOTTACAHRN1, Hiroki GOTO1, Ryusho KARIYA1
1

Center for AIDS Research and Graduate School of Medical Sciences, Kumamoto University

Xenograft tumor models from patient-derived tumor tissue at low passage have been shown toconserve original tumor characteristics such as heterogeneous histology, clinical biomolecularsignature, malignant phenotypes and genotypes, tumor architecture and tumor vasculature. Patientderived tumor xenografts (PDX) are now believed to offer relevant predictive insights into clinicaloutcomes when evaluating the efﬁcacy of novel cancer therapies. NOD/Scid based immunodeﬁcient
mice (ex. NOD/Scid, NOG, NSG, and NOJ mice) have been used as the recipient of human tumortransplantation due to the high forming efficiency, however, these mice are relatively weak, shorter
life span and low breeding efﬁciency. We developed Balb/c Rag-1 Jak3 double deﬁcient (Balb/c RJ)
mice to cover these disadvantages. Breeding efficiency of Balb/c RJ mice are same as Balb/c miceand human hematopoietic cells and tumor cells are also successfully seeded and developed in Balb/c RJ mice. We transplanted patient derived cholangiocarcinoma (CCA) tissue into Balb/c RJ mice
subcutaneously, and 16 out of 20 cases formed tumors in mice, and 4 CCA cell lines were establishedfrom PDX tissue culture.
PDX model using Balb/c RJ mice can be the useful tool for cancer research and drug development.

– 40 –

26G-ISMS31 The Unbound Concentration of Multimodal Drugs in the Assay Medium Usedin the Multi-electrode Array System for Cardiac Risk Assessment with iPS Cellderived Cardiomyocytes○ Takashi YOSHINAGA1,4, Raku SINKYO2, Kiyomi KIKUCHI2, Tomohiko TANIGUCHI1,4,

Yuko SEKINO3,4, Kohei SAWADA1,4
1

Global CV Assessment, Eisai Co., Ltd., 2Global DMPK, Eisai Co., Ltd., 3Division of Pharmacology, National
Institute of Health Sciences, 4Japan iPS Cardiac Safety Assessment (JiCSA)

To characterize and predict the QT interval prolongation and proarrhythmia potential of drug candidates,
investigations into the challenges of using multi-electrode array system and human stem cell-derived
cardiomyocytes are on-going. Sometimes, discussions arise on whether assay results should beinterpreted using total (applied) or unbound concentrations to understand the compounds cardiovascularliabilities. To provide useful suggestions, we measured the unbound concentrations of 59 drugs which
include CiPA selected 29 compounds in the iCell Cardiomyocytes Maintenance Medium (CMM,
Cellular Dynamics International) including fetal bovine serum by equilibrium dialysis method using
Rapid Equilibrium Dialysis device (ThermoFisher Scientiﬁc). Then, unbound fraction (fu) values at low
and high concentrations (100-fold differences) in CMM were calculated. When saturation of bindingat the high concentration was observed, an additional experiment was done at a middle concentration.
Most of compounds showed similar fu values at low and high concentrations. On the other hand, several
compounds such as Mibefradil, Thioridazine, Bepridil, Prenylamine, Tolterodine, Haloperidol, andDronedarone showed more than 2-fold higher fu values at high concentrations than those at low ones.
Tamoxifene and Amiodarone showed very low fu values (less than 0.01) which indicated very strong
protein binding. Further analysis of the relationships between the fu values in CMM and human plasma
was conducted. Good correlation in rank order with non-linier correlation was obtained. These results
indicated that the actual unbound concentrations in CMM will be very useful to consider and interpretthe relationship to unbound plasma concentrations which caused CV events in human.

26G-ISMS32 Discovery of ASP3026, a Potent and Selective Anaplastic Lymphoma Kinase(ALK) Inhibitor○ Kazuhiko IIKUBO1, Yutaka KONDOH1, Itsuro SHIMADA1, Takahiro MATSUYA1,

Kenichi MORI1, Yoko UENO1, Sadao KUROMITSU1, Minoru OKADA1
1

Astellas Pharma Inc.

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancers,
including echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small celllung cancer. We synthesized a series of 1,3,5-triazine derivatives and discovered ASP3026 as apotent and selective ALK inhibitor, which demonstrated dose-dependent antitumor activity in micebearing NCI-H2228 tumor xenografts. ASP3026 also showed inhibitory activity against the L1196M
gatekeeper mutant of ALK. Syntheses and structure-activity relationships of 1,3,5-triazine derivatives
and computational modelings of ASP3026 will be presented.

– 41 –

26G-ISMS33 Immune Proﬁling with a New NGS-based Repertoire Analysis○ Takaji MATSUTANI1, Kazutaka KITAURA1, Hiroshi YAMASHITA1, Hitomi AYABE1,
Hiroyuki SATO1, Yuichi MORITA1, Tadasu SHINI2,3, Ryuji SUZUKI1,3
1

Repertoire Genesis Incorporation, 2BITS. Co., Ltd., 3Clinical Research Center for Rheumatology and Allergy,
Sagamihara National Hospital

NGS-based TCR and BCR repertoire analyses are powerful tools to analyze speciﬁcities and diversities
of T and B cells. Here, we developed a new TCR/BCR repertoire analysis methods using unbiased
ampliﬁcation (adaptor-ligation PCR) and an in-house developed analysis software following a pairedend MiSeq sequencing. This method enables a highly accurate and quantitative analysis. With regard
to TCR, we examined gene usage, diversity and similarity of TRA/TRB repertoires with PBMCs of
20 healthy individuals. TRA repertoires were more similar between individuals than TRB repertoires
were. The inter-individual similarity of TRA depended largely on the frequent presence of shared TCRs
among two or more individuals. The shared TRA sequences often contained invariant TCRα derived
from invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells. Regarding
BCR, we sequenced ﬁve isotypes of IgH (IgM, IgD, IgG, IgA and IgE) in 12 individuals and analyzed
frequencies of somatic hypermutation (SHM) among Ig subclasses. Shared sequences were frequently
observed within multiple Ig subclasses and the frequency of SHM varied among the Ig subclasses.
Respite the sequential class-switch recombination (CSR) from upstream to downstream subclasses, theshared clones had the almost same SHM levels while subclass-speciﬁc clones had a different levels of
SHM dependent of genomic location. These results gave us an interesting insight into the development
and the maturation of B cells. In conclusion, NGS-based TCR/BCR repertoire analysis will provide us
critical information on T and B cells playing a pivotal role in immune system.

26G-ISMS34 Cyclodextrin-based Supramolecular Drug Carriers and Active Pharmaceutical

Ingredients○ Taishi HIGASHI1, Keiichi MOTOYAMA1, Hidetoshi ARIMA1,2
1

Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University,
Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented)
Program”, Kumamoto University
2

Cyclodextrins (CyDs) are cyclic oligosaccharides composed of six (α-CyD), seven (β-CyD), and eight(γ-CyD) glucopyranose units that can form inclusion complexes with various organic and inorganic
compounds. Recently, we have developed CyD-based supramolecular drug carriers for low-molecularweight drugs, peptide/protein drugs, gene and nucleic acid drugs through the combination withfunctional polymers or macromolecules, such as dendrimer, polyethylene glycol (PEG) and liposome(Fig. 1). Moreover, we also utilized CyDs as active pharmaceutical ingredients. In this presentation,
we introduce the recent applications of CyDs as drug carriers
and active pharmaceutical ingredients. The topics of thepresentation are shown as follows.
1) Folate-appended CyDs as drug carriers for low-molecularweight anticancer drugs
2) Reversible PEGylation for peptide/protein drugs based on
CyD/adamantane interaction3) Polypseudorotaxane hydrogels as a stabilizer for antibodies
4) Ligand-appended dendrimer/CyD conjugates as gene andnucleic acid drugs carriers5) Folate-appended CyDs as tumor-selective anticancer drugs– 42 –

26G-ISMS35 Antifungal Activities and Nonclinical Pharmacokinetics of APX001A/APX001(E1210/E1211), a New Broad-Spectrum Antifungal, with a New Mode of Action○ Takaaki HORII1
1

Global Health Research Section, hhc Data Creation Center, Eisai Co., Ltd.

APX001A (formerly known as E1210) inhibited the inositol acylation of fungus-specificglycosylphosphatidylinositol (GPI), which is catalyzed by Gwt1p, leading to the inhibition of GPIanchored protein maturation. The compound not only inhibited fungal growth, but also suppressed
the expression of some virulence factors of fungi. APX001A demonstrated potent, broad-spectrum
antifungal activity against clinically important fungi, including Candida spp., Aspergillus spp., andother filamentous fungi. It showed no cross-resistance with azoles and echinocandins. APX001(formerly known as E1211) is a water-soluble prodrug of APX001A, and efficiently converted to
APX001A in animals, and in human S9 tissue fractions in vitro. APX001 was effective in murine
models of candidiasis, aspergillosis, fusariosis, and scedosporiosis. Furthermore, APX001/ APX001A
demonstrated synergy in combination with other antifungals in vitro and in vivo against Candida spp.
and Aspergillus spp. Amplyx Pharmaceuticals was licensed E1211 and E1210 from Eisai in 2015, andrenamed APX001 and APX001A, respectively. Amplyx is now advancing the evaluation of APX001 in
Phase 1 program using both IV and oral formulations to address the need for hospital administration, as
well as continued dosage after hospital discharge. Amplyx plans to initiate Phase 2 studies in 2017.

26G-ISMS36 Synthesis and Evaluation of Potent, Orally Available, Well-balanced EP2 andEP3 Dual Agonists○ Akihiro KINOSHITA1, Masato HIGASHINO1, Koji YOSHIDA1, Yoshiyuki ARATANI1,

Akito KAKUUCHI1, Keisuke HANADA1, Hiroyuki TAKEDA1, Toshikiko NISHIYAMA1,
Hidekazu MATSUYA1, Kazuyuki OHMOTO1
1

Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd.

Our purpose was to develop PGE2 analogs possessing highly potent dual EP2 and EP3 agonist
activity with selectivity against the other two subtypes (EP1 and EP4), because a dual EP2 and EP3
agonist is expected as an effective therapeutics addressing unmet medical needs for treatment of aunderactive bladder (UAB). While no dual EP2 and EP3 agonist has been reported, a dual EP2 and EP4
agonist with selectivity against the EP1 and EP3 receptor subtypes was reported in 20121. At ﬁrst, we
synthesized cyclic carbamate derivatives having cyclobutyl group and terminal ﬂuorine atom in orderto reduce EP4 agonist activity and add EP3 agonist activity, and then replaced the core structure withcyclopentanone for enhancement of orally absorption. The resulting compound, ONO-8055, showed
excellent potency (human EC50 EP2 = 0.67 nM，EP3 = 0.7 nM), EP1 and EP4 subtype selectivity(>400-fold) and good pharmacokinetic proﬁles. Regarding in vivo efﬁcacy, ONO-8055 improved thelower urinary tract dysfunctions of neurogenic underactive bladder in a rat lumber spinal stenosis (LCS)
model2. Furthermore, as a result of Phase I trial in Europe, there was no safety or PK concern. ONO8055 is currently under development as a new highly promising UAB drug.
1)
Kambe, T.; Maruyama, T; Nakai, Y; Oida H.; Maruyama T.; Abe N.; Nishiura, A.; Nakai, H.; Toda, M.
Bioorganic & Medicinal Chemistry , 2012, 20 , 3502.
2)
Sekido N.; Kida J.; Mashimo H.; Wakamatsu D.; Okada H.; Matsuya H.; J Urol, 2016, 196 , 609.
– 43 –

26G-ISMS37 Novel Development of Chemotherapy for Relapsed and Refractory AML Basedon the Promising Functional Mechanism of Cytidine Analog, DFP-10917○ Masakazu FUKUSHIMA1, Kenzo IIZUKA1, Chung ZHANG1, Cheng JIN1,

Kiyoshi ESHIMA1
1

Division of Research and Development, Delta-Fly Pharma, Inc.

Acute myeloid leukemia (AML) is still progressed disease vigorously challenging to urgently improvea prognosis in patients. At present time, induction-chemotherapy with cytarabine (one of cytidine
analog) combined with anthracycline drugs has been frequently conducted for the treatment of AML,
and sequential consolidation-chemotherapy with almost same regimen is performed for patients.
However there are few suitable treatment options for patients with relapsed and refractory AML.
We developed a new generation of cytidine-type antitumor nucleoside, DFP-10917 and investigated
the antitumor efﬁcacy and functional mechanism of this drug in vitro and in vivo using human tumor
cells. DFP-10917 showed the most potent antitumor activity on tumor models in mice following its
prolonged (14-days) infusion at very low-dose (4.5 mg/kg/day) compared to short injection of DFP10917 and of other cytidine analog. Under such prolonged dosing schedule, DFP-10917 is converted toits nucleotide form and subsequently incorporated into DNA in tumor cells which cause DNA-strand
breaks resulting in G2/M phase-arrest by cellular checkpoint regulators and resultantly formed theultimate apoptotic cells. In contrast, cytarabine is converted to their nucleoside-triphosphates and theninhibit DNA polymerase activity leading to protection of DNA biosynthesis during the S-phase of thecell cycle.
To evaluate clinical efﬁcacy and toxicity in phase I/II study of DFP-10917, AML patients were treated with
continuous infusion (CI) of DFP-10917. In phase I study, low-dose (6 mg/m2) 14-day CI of DFP-10917
was found to result in a clinical beneﬁt to patients as recommended dose and schedules. In phase II study,
total 29 patients were enrolled and the response rate and the median survival time in relapsed/refractory
AML patients were 48% and 7.3 months, respectively. No patients discontinued DFP-10917 treatment due
to unacceptable drug-related toxicity. Further study of DFP-10917 in a phase III study in AML is planned.

26G-ISMS38 System-wide Temporal Characterization of the Phosphoproteome ofNon-small-cell Lung Cancer Cells Treated with Erlotinib○ Adachi JUN1, Yuichi ABE1, Maiko SHIMIZU1, Marina KISHIDA1, Ayako SATO1,

Takeshi TOMONAGA1
1

Laboratory of Proteome Research National Institutes of Biomedical Innovation, Health and Nutrition

Phosphoproteome is one of key signatures to understand the mode of action and mechanism of drug
resistance of kinase inhibitors at the molecular level, pathway level and system level. We developed
sensitive and high-throughput phosphoproteome and tyrosine phosphoproteome analysis platform andperformed temporal characterization of non-small-cell lung cancer cell lines treated with erlotinib.
We obtained phosphoproteome and phosphotyrosine-proteome proﬁles of two erlotinib-sensitive cells
and four erlotinib-resistant cells treated by erlotinib for 0 h, 6 h and 24 h. We quantiﬁed over 12000
phosphorylation sites by phosphoproteome analysis and over 600 phosphorylation sites on tyrosine
residue by phosphotyrosine-proteome.
We extracted kinases and other enzymes which are up-regulated in resistant cells and selected 46
inhibitors for drug screening. 24 of 46 inhibitors inhibited cell growth of at least one resistant cell line.
Our sensitive and high-throughput phosphoproteome and tyrosine phosphoproteome analysis platform
has a potential to identify pharmacoproteomic markers of drug efficacy as well as candiates ofmolecular targets to overcome drug resistance.

– 44 –

26G-ISMS39 Identiﬁcation of WAC-224, a Novel Anticancer Quinolone as a Human

Topoisomerase II Inhibitor○ Tomonori YAMAGUCHI1, Kenji ITOH1, Taichi UESHIMA1, Rumiko SHIMABARA1,

Yohei KAWAKUBO1, Masayuki SATO1, Junpei YAMASHITA1, Tatsuya HIRANO1,
Akira YAZAKI1
1

Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.

Topoisomerese II inhibitors, such as Anthracyclines, are an important class of chemotherapeutic
agents, which are employed for the treatment in multiple types of cancers including acute myeloid
leukemia (AML). However, the therapeutic applications of Anthracyclines are limited because ofa cumulative cardiotoxicity and an efflux-mediated drug resistance. WAC-224 is a novel anticancer
quinolone derivative targeting human topoisomerase II and has the superior characteristics in potency
and safety both in vitro and in vivo compared with Vosaroxin (QINPREZO®, formerly SNS-595),
which showed lower potential for cardiotoxicity in the clinical trials. In our evaluations, WAC-224 hadhigher selectivity for cancer cells versus normal cells in its antiproliferative activity; the IC50 value was
1.4 nM for MV4-11 AML cell line versus > 50 μM for MRC-5 normal cell line. WAC-224 also showed
the potent in vitro activity against multi drug-resistant cell lines such as MES-SA/Dx-5. Additionally,in vivo murine xenograft studies conﬁrmed the potent therapeutic effects of WAC-224 for therapy ofdifferent types of cancers including multi-drug resistant one. These results suggest that WAC-224 is apotentially effective therapeutic agent for leukemia and multi-drug resistant cancers.

26G-ISMS40 Lenvatinib Mesilate (LEN) Enhanced Antitumor Activity of a PD-1 Blockade

Agent by Potentiating Th1 Immune Response○ Yu KATO1, Xingfeng BAO2, Shannon MACGRATH2, Kimiyo TABATA1, Yusaku HORI1,

Sho TACHINO1, Mark MATIJEVICI2, Yasuhiro FUNAHASHI1, Junji MATSUI1
1

Eisai Co., Ltd., Tsukuba, Ibaraki, Japan, 2Eisai Inc. Andover, MA, USA

Lenvatinib (LEN) selectively inhibits the kinase activities of VEGFR1-3, FGFR1-4, KIT, PDGFRα,and RET, which are involved in tumor angiogenesis and tumor cell proliferation in several cancer types.
Currently, Phase 1b/2 clinical trials of the combination of LEN and pembrolizumab (a monoclonal
antibody [mAb] that blocks the interaction between PD-1 and its ligands) are ongoing for selected
types of cancer including renal cell carcinoma, melanoma and non-small cell lung carcinoma, etc.
In this study, we will report that tumor associated macrophage and regulatory T cell population were
downregulated by treatment of LEN, and combination of LEN with PD-1 mAb showed more potent
antitumor activity in CT26 mice tumor syngenic model compared with either single treatment alone.
Notably, complete tumor regressions were detected in some mice with combination treatment in the
H22 mice tumor syngenic model. Re-inoculation of fresh H22 cells into these cured mice was rejected.
BioMap analysis showed that PD-1 mAb increased both Th1 and Th2 cytokines, LEN decreased Th2
cytokines, and combination treatment increased Th1 cytokines but decreased Th2 cytokines.
The results indicate that the combination of LEN with PD-1 mAb was more effective than single-agent
treatment in multiple syngeneic tumor models and was accompanied with a potent antitumor immune
response.
– 45 –

26G-ISMS41 Identiﬁcation of Blood-based Gene Expression Biomarkers for Major Depressive

and Bipolar Disorders○ Seiji NAKAMURA1, Hiroaki HORI2, Yohei ISHIZAWA1, Kenichi MATSUBARA1,

Ryo MATOBA1, Hiroshi KUNUGI2
1

DNA Chip Research Inc., 2Department of Mental Disorder Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry

Major depressive and bipolar disorders are typical psychiatric problems affecting about 350 million
people globally. Pathogenesis is not fully understood and laboratory tests for diagnosis and prognosis
are not established. We have performed microarray analysis using blood samples of major depressive
and bipolar disorder (n=25) patients against age, gender-matched healthy controls (n=25). Genes related
to ribosomes were found to be up-regulated in patients of major depressive and bipolar disorders.
Ribosomal proteins RPL17 and RPL34 were further validated by qRT-PCR using independent test
cohorts (15 patients each for depressive and bipolar against healthy controls). Reproducibility of theresult indicates that ribosomes related genes could serve as useful screening biomarkers.

26G-ISMS42 Anti-Helicobacter Pylori Activity of a Novel Derivative of Intervenolin○ Tomokazu OHISHI1, Toru MASUDA1, Shun-ichi OHBA1, Chigusa HAYASHI2,
Hikaru ABE3, Masayuki IGARASHI2, Takumi WATANABE3 , Daniel Ken INAOKA4, Kiyoshi
KITA5, Masakatsu SHIBASAKI3, Manabu KAWADA1,6
1

Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation,
Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, Microbial Chemistry Research
Foundation, 3Institute of Microbial Chemistry (BIKAKEN), Laboratory of Synthetic Organic Chemistry,
Microbial Chemistry Research Foundation, 4Center for International Collaborative Research, Nagasaki
University, 5School of Tropical Medicine and Global Health, Nagasaki University, 6Institute of Microbial
Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation
2

Colonization and infection of Helicobacter pylori (H. pylori ) is a major cause of gastric diseases including
gastritis, peptic ulcers, and gastric cancer. Therefore, eradication of H. pylori leads to prevention of gastricdiseases. Although standard treatment for H. pylori involves a combination of antibiotics, they kill mostbacteria in our body, leading to the occurrence of side effects. We previously found that an antitumor
agent intervenolin (ITV) also exhibits selective anti-H. pylori activity. Here we demonstrate that a novel
derivative of ITV showed selective anti-H. pylori activity like ITV without any effect on other bacteria
including intestinal bacteria. Interestingly, oral monotherapy of the ITV derivative had a stronger anti-

H. pylori activity without any side effects in a mouse H. pylori -infection model than that of ITV and thestandard triple therapy of a proton pump inhibitor and two antibiotics. These results suggest that the ITVderivative would be a new potential therapeutic agent for H. pylori infection treatment. Now, we aretrying to identify a molecular target of the ITV-derivative against H. pylori .

– 46 –

26G-ISMS43 Discovery of Novel 5,6,7,8-tetrahydro[1,2,4]Triazolo[4,3-a ]Pyridine Derivatives asγ-secretase Modulators○ Takafumi TAKAI1, Tatsuki KOIKE1, Minoru NAKAMURA1, Yasutaka HOASHI1,
Yoshihide TOMATA1, Sachie MORIMOTO1, Yuichi KAJITA1, Toshiro YAMASHITA1,
Naohiro TAYA1, Tetsuya TSUKAMOTO1, Tomomichi WATANABE1, Koji MURAKAMI1,
Tomoko IGARI1, Makoto KAMATA1
1

Takeda Pharmaceutical Company Limited

γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the

production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimerʼs disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a ]pyridine derivatives was
discovered and characterized as GSMs. The optimization study using ligand-lipophilicity efficiency(LLE) as a drug-likeness guideline led to identiﬁcation of various types of high-LLE GSMs with potent
in vivo Aβ42-lowering effects by single administration. Furthermore, multiple oral administration of
the representative compound signiﬁcantly reduced soluble and insoluble brain Aβ42, and ameliorated
cognitive deﬁcit in novel object recognition test (NORT) using Tg2576 mice as an AD model.

26G-ISMS44 Regulatory Science for R&D Promotion of Innovative Pharmaceuticals*
Kazuhiko MORI1, Takao YAMORI2, ○ Toru KAWANISHI3, Takao INOUE4
1

Ministry of Health, Labor and Welfare (MHLW), 2Pharmaceuticals and Medical Devices Agency (PMDA),
National Institute of Health Sciences (NIHS), 4Japan Agency Medical Research and Development (AMED)

3

At present the nation ʼ s policy for research and development (R&D) promotion of innovative
pharmaceuticals and improvement of environments for the R&D is formulated by Japanese
government. In the policy the enhancement and promotion of Regulatory Science (RS) touching theappropriate and rapid predict, evaluate, and judgment of quality, efﬁcacy and safety of pharmaceuticals
is especially stressed. Following the nationʼs policy, the MHLW is promoting the strategy package(Strategy of SAKIGAKE) facilitating all the process from R&D, clinical research/trials, pre- andpost- marketing safety, insurance coverage, through globalization of innovative products which are
to be put into practical use, targeting innovative pharmaceuticals which can cure serious illnesses. In
concert with the MHLW, the PMDA is building up the systems, such as priority consultations, priorassessment, and priority reviews. The PMDA is taking various approaches such as the introductionof data mining methods and safety evaluation of drugs based on pharmaco-epidemiological methods
utilizing electronic medical records, or construction of medical information database (MID-NET), toenhance and advance safety measures. The PMDA has also established the Science Board consistingof external experts to discuss the evaluation methods of innovative drugs. The pharmaceuticals-related
divisions in the NIHS have carried out RS research to develop the point-to-consider documents or
standardized methods for evaluating mainly quality and non-clinical safety of innovative products suchas nanomedicines, fully engineered protein drugs, oligonucleotide drugs, and so on. The AMED is
supporting about 80 research projects by the Grant Program naming “Research on Regulatory Scienceof Pharmaceuticals and Medical Devices”.
*The poster is presented by Division of Regulatory Science, Pharmaceutical Society of Japan.
– 47 –

Appendix

Abstracts Presented by English in 137th Annual Meetingof the Pharmaceutical Society of Japan1. Programs
Special Lectures
Sunday, 26 March

Room A (Sendai International Center Conference Bldg 2F)【Main Hall】

9:00 － 10:00

SL-2

Designed Probes for Measuring and Controlling DNA Damage Repair
Eric Kool（Stanford University）

Sunday, 26 March

Room A (Sendai International Center Conference Bldg 2F)【Main Hall】

14:30 － 15:30

SL-5

Genotypic Variability and the Quantitative Proteotype
Ruedi Aebersold（ETH Zurich / University of Zurich）

Sunday, 26 March

Room A (Sendai International Center Conference Bldg 2F)【Main Hall】

15:45 － 16:45

SL-6

The Functionalization of C-H Bonds
Christina White（University of Illinois）

Sunday, 26 March

Room M (Tohoku University Centennial Hall 2F)【Kawauchi Hagi Hall】

9:00 － 10:00

SL-7

Evolution of Orbitrap mass spectrometry and its future perspectives
Alexander Makarov（Thermo Fisher Scientific）– 50 –

Symposium
Sunday, 26 March 9:00 － 11:30

Room J (Sendai International Center Exhibition Bldg 1F)【Meeting Room 1】

Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
Organizer: Ikuro ABE
OS23-1

9:00 － 9:40

Complexity Generation in Fungal Natural Product Biosynthesis - New Enzymatic Reactions○ Yi TANG1（1Department of Chemical and Biomolecular Engineering and Department of Chemistry andBiochemistry, University of California, Los Angeles）

OS23-2

9:40 － 10:15

OS23-3

10:15 － 10:55

Redesigning Complex Natural Products Biosynthesis○ Ikuro ABE1（1The Univ. Tokyo, Grad. Sch. Pharm. Sci.）
The Creation of New Functional Molecules by Rational Design at Protein-Protein
Interface of Fatty Acid Synthase and Polyketide Synthase○ Shiou-Chuan (Sheryl) TSAI1（1Departments of Chemistry, Molecular Biology and Biochemistry, andPharmaceutical Sciences, University of California, Irvine）

OS23-4

10:55 － 11:30

Phytochemical Genomics: A Basis for Redesign of Plant Natural Products Biosynthesis○ Kazuki SAITO1,2（1Chiba Univ., Grad. Sch. Pharm. Sci., 2RIKEN CSRS）

Sunday, 26 March 15:00 － 17:30

Room D (Sendai International Center Conference Bldg 3F)【Shirakashi 1】

FIP forum 2017: International educational trends for pharmaceutical researchers in the next generation
Organizer: Masaru KATO
Opening remarks
15:00 － 15:05
Masaru KATO1（1Univ. Tokyo, Grad. Sch. Pharm. Sci.）
OS33-1
Pharmacy education in the US, a hint for reevaluating the Japanese system
15:05 － 15:35○ Tomohiko OHWADA1, Erika S. CHAN1,2（1Univ. Tokyo,  Grad. Sch. Pharm. Sci., 2Rutgers Univ., Schoolof Pharmacy）

OS33-2

15:35 － 16:05

Break

Pharmacy education in Korea; Challenges for a better future○ Kyungim KIM1（1Korea Univ., College of Pharm.）

16:05 － 16:10

OS33-3

16:10 － 16:40

OS33-4

16:40 － 17:10

Current status and perspectives of the 6-year pharmaceutical education: Aiming totrain pharmacist-scientist○ Ken-ichi INUI1,2（1Professor Emeritus of Kyoto Univ., 2Professor Emeritus of Kyoto Pharmaceutical Univ.）
Education and workforce development○ William N. CHARMAN1,2（1Monash Univ., Faculty Pharm. and Pharm. Sci., 2FIP Education Executive
Committee）

Closing discussions
17:10 － 17:30
Masaru KATO1（1Univ. Tokyo, Grad. Sch. Pharm. Sci.）– 51 –

Monday, 27 March 9:00 － 11:30

Room J (Sendai International Center Exhibition Bldg 1F)【Meeting Room 1】

PSJ-PSK Joint Symposium: The mechanism, evaluation, prediction and diagnosis of drug-induced
liver injury
Organizer: Kouichi YOSHINARI
Introduction
9:00 － 9:02

OS42-1

9:02 － 9:39

OS42-2

9:39 － 10:16

OS42-3

10:16 － 10:53

OS42-4

10:53 － 11:30

Kouichi YOSHINARI1（1Sch Pharmaceut Sci, Univ Shizuoka）

Role of nuclear recptors in drug-induced liver injury
Kouichi YOSHINARI1（1Sch Pharmaceut Sci, Univ Shizuoka）
Chemical-induced abnormal lipid metabolism and multiple metabolic toxicities○ Byung-Hoon LEE1（1College of Pharmacy, Seoul National University, Korea）
Prediction of metabolism-dependent hepatotoxicity using human liver microsomes○ Sang Kyum KIM1（1College Pharm, Chungnam Natl Univ）
Diagnostic and therapeutic potential of miRNAs for liver injury○ Miki NAKAJIMA1（1Kanazawa Univ. Facl. of Pharm. Sci.）

Saturday, 25 March 13:15 － 15:15 Room O (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【Lecture room】
New Trends of Natural Products Chemistry ― Redesign of Biosynthesis
Organizer: Kenji WATANABE, Masahiro OKADA
S14-1

13:15 － 13:45

Identification of Novel Diels Alderases from Fungal Biosynthetic Pathways

Masao OHASHI1, Kenji WATANABE1, Ken HOUK2, ○ Yi TANG2（1University of Shizuoka, 2UCLA）

Sunday, 26 March 13:15 － 15:15

Room L (Sendai International Center Exhibition Bldg 1F)【Meeting Room 3】

Cutting edge of retinal circuit research
Organizer: Fumitaka OSAKADA, Chieko KOIKE
S31-4

14:35 － 15:15

The unique pharmacology of synapses in the outer retina○ Steve H. DEVRIES1（1Northwestern University Feinberg School of Medicine）

Monday, 27 March 13:15 － 15:15

Room O (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【Lecture room】

Frontier of biomedical science by biomolecule analysis based on mass spectrometry
Organizer: Masamitsu MAEKAWA, Masaru MORI
S54-4

14:15 － 14:35

Screening of lipid hydroperoxide-mediated protein modification using stable isotope labelingby fatty acids in cell culture (SILFAC) coupled with isotope pattern dependent scan
○ Seon Hwa LEE1, Ryo TAKAHASHI1, Tomoyuki OE1（1Tohoku Univ. Grad. Sch. of Pharm. Sci.）– 52 –

Oral Presentation
Saturday, 25 March
25F-pm08S
14:39 － 14:51

Room F (Sendai International Center Conference Bldg 3F)【Meeting Room 8】

Tetrandrine potentiates the glucocorticoid efficacy via P-glycoprotein and MAPK
inhibition in mitogen-activated human peripheral blood mononuclear cells○許 文成 1,2, 孟 科含 1, 塗 遠超 2, 田中 祥子 1, 恩田 健二 1, 杉山 健太郎 1, 平野 俊彦 1, 山田 陽城 112

（ 東京薬大薬 , 湖北省中医病院薬）

Saturday, 25 March
25H-pm16
16:15 － 16:27

Room H (Sendai International Center Conference Bldg 1F)【Meeting Room 1】

Controlled delivery of insulin by liposome within thermoreversible hydrogel after
subcutaneous administration○楊 智鈞 1, 呂 愛平 1, 趙 中振 1, 陳 暁昱 1（1香港浸会大学中医薬学院）

Saturday, 25 March

Room P (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C101】

25P-am02S Study of reaction between 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and tertiary
9:12 － 9:24
amines by LC-MS○ Xiaomin LI1, Yayoi KANBAYASHI2, Zekun YANG1, Muneki ISOKAWA1, Chao WANG1,3,
Takashi FUNATSU1, Masanobu UCHIYAMA1,3, Makoto TSUNODA1（1Graduate School of2

3

Pharmaceutical Sciences, The University of Tokyo, Institute of Innovation, Ajinomoto Co., Inc., Riken）

25P-am08S LC/ESI-MS approach for characterization of Angiotensin II-induced lipid peroxidation
10:24 － 10:36
in human endothelial cells○藤岡 修平 1, 髙橋 亮 1, 大江 知行 1, 李 宣和 1（1東北大院薬）

Saturday, 25 March
25R-pm15
16:03 － 16:15

Room R (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C105】

What does a complete quantum mechanical binding analysis of dipeptidyl peptidase IV
with antidiabetic drugs conclude?
○ Arulmozhiraja SUNDARAM1,2, Naoya MATSUO1, Seiji OKAZAKI1,2, Hitoshi SHIMANO3,4,
Hiroaki TOKIWA1,2,4（1Department of Chemistry, Rikkyo University, 2Research Center for Smart Molecules,
3

Rikkyo University, Department of Internal Medicine (Endocrinology and Metabolism), University of Tsukuba,
4
AMED-CREST）

Saturday, 25 March
25T-pm04
13:51 － 14:03

25T-pm11
15:15 － 15:27

25T-pm16
16:15 － 16:27

Organocatalytic Asymmetric Desymmetrization of Alkane-1,n-Bisphenols via Aromatic
Bromination: Enantiotopic Group Differentiation of  Distal Bisphenols○ Harisadhan GHOSH1, 川端 猛夫 1（1京大化研）
Regiocontrol of the deoxyfluorinative rearrangement reactions of 4,4-disubstituted
2-hydroxycyclohexa-2,5-dieneones into ortho-fluorophenols○ Ahmed ABUBAKR1, 斉藤 和幸 1, 田窪 景太 1, 赤井 周司 1（1大阪大学大学院薬学研究科）
Activation and stabilization of Pd nanoclusters for reaction under milder conditions○ Sangita KARANJIT1, 柏原 雅也 1, 中山 淳 1, 難波 康祐 1（1徳島大薬）

Saturday, 25 March
25U-pm03
13:39 － 13:51

Room T (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C201】

Room U (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C202】

Direct Catalytic Asymmetric Aldol Reaction of Amides○ Zijian LIU1, Toshifumi TAKEUCHI1, Roman Krzysztof PLUTA1,
1 1
微生物化学研究所）
Fernando Arteaga ARTEAGA1, Naoya KUMAGAI1, Masakatsu SHIBASAKI（– 53 –

Saturday, 25 March
25V-pm07
14:27 － 14:39

Room V (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C205】

Lysophosphatidic acid promotes IL-10 expression in a mouse LPS model○王 嬌 1, 可野 邦行 1, 佐竹 響子 1, 青木 淳賢 1（1東北大院薬）

Saturday, 25 March

Room W (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C206】

25W-pm05

The mevalonate pathway regulates primitive streak formation via protein farnesylation○虞 若星 1, 岡本 ‐ 内田 好海 1, 仁科 博史 1（1東京医歯大学難治研）
25W-pm09S Investigation of anti-fibrotic effects of cyclosporin A in pulmonary fibrosis
14:39 － 14:51○山崎 璃沙 1, 粕谷 善俊 2, 藤田 哲雄 2,3, 梅澤 弘毅 2,3, 柳原 まどか 1, 中村 浩之 1, 吉野 一郎 4,
巽 浩一郎 3, 村山 俊彦 1（1千葉大院薬・薬効薬理 , 2千葉大院医・分子生体制御 , 3千葉大院医・呼内 , 4千葉大院医・
13:51 － 14:03

呼外）

25W-pm13S Expression of NEAT1 is significantly higher in MCPyV-positive Merkel cell carcinoma
15:27 － 15:39
than MCPyV-negative one.
○秋月 源 1, 今村 亮俊 2, 山田 俊理 3, 水谷 玲奈 3, 松下 倫子 1, 長田 桂子 1, 桑本 聡 1, 加藤 雅子 1,
秋光 信佳 3, 林 一彦 1（1鳥取大医 , 2千葉大薬 , 3東京大薬）

Sunday, 26 March
26F-am08
10:24 － 10:36

Room F (Sendai International Center Conference Bldg 3F)【Meeting Room 8】

The effects of arsenic disulfide alone and combined with tetrandrine on viabilities of
2D- and 3D-cultured MCF-7 breast cancer cells○趙 玉雪 1,2, 恩田 健二 1, 田中 祥子 1, 袁 博 3, 清海 杏奈 4, 大野 保奈美 1, 植松 南美 1,
杉山 健太郎 1, 平野 俊彦 1（1東京薬科大学薬学部臨床薬理学教室 , 2中国中医科学院鍼灸研究所 , 3東京薬科大学
4

薬学部応用生化学教室 , 東京薬科大学薬学部医薬品安全管理学教室）

Sunday, 26 March

Room P (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C101】

26P-am07S Development of stealth shell based on polycarboxybetaine structure tuned to
10:12 － 10:24
selectively interact with cells in tumor extracellular acidic pH○ Abdul-Hackam RANNEH1, 武本 宏泰 1, 野本 貴大 1, 松井 誠 1, 友田 敬士郎 1, 西山 伸宏 1
1

（ 東工大院化生研）

Sunday, 26 March
26Q-am03
9:24 － 9:36

Room Q (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C102】

Quassinoids: Viral Protein R Inhibitors from Picrasma javanica Bark Collected in
Myanmar○ Nwet Nwet WIN1,2, Takuya ITO1, Takeshi KODAMA1, Yi Yi WIN2, Hla NGWE2,
Hiroyuki MORITA1（1Division of Natural Products Chemistry, Institute of Natural Medicine, University of2Toyama, Department of Chemistry, University of Yangon, Myanmar）

26Q-am04
9:36 － 9:48

New diterpenoids from Plectranthus scutellarioides collected in Indonesia○ Kartika SENDA1, Takuya ITO1, Hiroyuki MORITA1（1富山大学和漢研）

26Q-am12S Synthesis of the glycosyl fattyacids for Mincle-ligand obtained from the pathogenic
11:12 － 11:24
fungus Malassezia○ Huy LE VAN1, 田中 千晶 1, 山﨑 晶 2, 宮本 智文 1（1九大院薬 , 2九大生医研）
26Q-pm03
PPARα expression influences on atrophy of the mouse uterus by Astragalus
13:39 － 13:51
mongholicus  root - treatment○ Banzragchgarav ORKHON1, Kyoko KOBAYASHI1, Batkhuu JAVZAN2, Sasaki KENROH1
1

2（ 東北医薬大 , モンゴル国立大学）– 54 –

Sunday, 26 March
26R-pm06
14:15 － 14:27

26R-pm16
16:15 － 16:27

Room R (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C105】

Development of Near-Infrared Photoactivatable Oxygenation Catalyst Targeting
Amyloid-β○倪 積智 1,2, 谷口 敦彦 1,2,3, 小澤 柊太 1, 堀 由起子 1, 富田 泰輔 1, 國信 洋一郎 1,2, 相馬 洋平 1,2,
金井 求 1,2（1東大院薬 , 2JST-ERATO, 3東京薬大薬）
Potent Mechanism-Based Sirtuin 2-Selective Inhibition by an in Situ Generated
Occupant of Selectivity Pocket, Substrate-Binding Site, and NAD+-Bindig Pocket.
○ Paolo MELLINI1, 伊藤 幸裕 1, 津元 裕樹 2, 李 頴 1, 鈴木 美紀 1, 徳田 奈津子 3, 柿澤 多恵子 4,
三浦 ゆり 2, 竹内 淳 3, Maija LAHTELA-KAKKONEN5, 鈴木 孝禎 1（1京府医大院医 , 2都健康長寿医セ
3

4

5

研 , 小野薬品工業 , 早稲田大学理工 , イースタンフィンランド大薬）

Sunday, 26 March
26T-pm13
15:39 － 15:51

Room T (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C201】

Copper(I)-Catalyzed Dehydrative C-Glycosidation of Unprotected Pyranoses with
Ketones○謝 瀟葦 1, 魏 暁峰 1, 施 世良 2, 清水 洋平 1, 金井 求 1（1東大院薬 , 2中国科学院上海有機化学研究所）

Sunday, 26 March

Room U (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C202】

26U-am01

Direct Catalytic Asymmetric Mannich-Type Reaction of α -Chlorinated andBrominated Amides○孫 博 1, Pandur Venkatesan BALAJI1, 熊谷 直哉 1, 柴崎 正勝 1（1微化研）
26U-am10S Structure determination of bicyclic proline blocked α -amino acid peptide
10:48 － 11:00○ザイ ルーハン 1, 尾谷 優子 1, 竹内 恒 2, 嶋田 一夫 1, 大和田 智彦 1（1東大院薬 , 2産業技術総合研究所）
26U-pm02
Direct α -Oxy C(sp3)-H Functionalization via Photoredox and Nickel Catalysis
13:27 － 13:39○孫 仲冬 1, 熊谷 直哉 1, 柴﨑 正勝 1（1微生物化学研究所）
9:00 － 9:12

Sunday, 26 March
26V-pm09
14:51 － 15:03

Catalytic Asymmetric Total Synthesis of Leptolyngbyolide C○崔 進 1, 渡辺 匠 1, 柴﨑 正勝 1（1微化研）

Monday, 27 March
27I-pm02

13:27 － 13:39

Room V (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C205】

Room I (Sendai International Center Conference Bldg 1F)【Meeting Room 2】

Characterizing topology of surface ligands on liposomes○李 尚軒 1, 佐藤 悠介 1, 兵藤 守 1, 原島 秀吉 1（1北大院薬）

Monday, 27 March

Room Q (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 1F)【C102】

27Q-am03S New acylated lignans from Mongolian Gobi plant Brachanthemum gobicum
9:24 － 9:36
○ Batsukh ODONBAYAR1, 村田 敏拓 1, Javzan BATKHUU2, 佐々木 健郎 1（1東北医薬大 , 2モンゴル国立大）

27Q-pm06
14:15 － 14:27

An anti-mycobacterial sphingolipid and a new bromopyrrol alkaloid from anunidentified Indonesian marine sponge○ Delfly B. ABDJUL1,2, Hiroyuki YAMAZAKI1, Syu-ichi KANNO1, Ayako TOMIZAWA1,
Henki ROTINSULU2,3, Defny S. WEWENGKANG2, Deiske A. SUMILAT2, Kazuyo UKAI1,
Magie M. KAPOJOS3, Michio NAMIKOSHI1（1Tohoku Medical and Pharmaceutical University,
2

3

Sam Ratulangi University, University of Pembangunan Indonesia）– 55 –

27Q-pm07S Structures and biological activities of alkyl pyridinium alkaloids from an unidentified
14:27 － 14:39
Indonesian marine sponge○ Wilmar MAARISIT1,2, Delfly B. ABDJUL1,2, Hiroyuki YAMAZAKI1, Hajime KATO1,
Henki ROTINSULU2,3, Defny S. WEWENGKANG2, Deiske A. SUMILAT2, Kazuyo UKAI1,
Magie M. KAPOJOS3, Michio NAMIKOSHI1（1Tohoku Medical and Pharmaceutical University,
2

3

Sam Ratulangi University, University of Pembangunan Indonesia）

Monday, 27 March
27T-am07
10:12 － 10:24

27T-pm05
14:03 － 14:15

Room T (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C201】

Base-Induced Transformation of 2H-Azirines to Isoxazoles: Involvement of the
Deprotonation Pathway○寧 桜唐 1, 尾谷 優子 1, 大和田 智彦 1（1東大院薬）
Reversible Stereoselective Folding/Unfolding Fueled by the Interplay of
Photoisomerism and Hydrogen Bonding○ Chris OPIE1, 熊谷 直哉 1, 柴崎 正勝 1（1微生物化学研究所）

Monday, 27 March

Room U (Tohoku University Kawauchi-Kita Campus Lecture Rooms C 2F)【C202】

27U-am05S synthesis and evaluation of novel halogenated pseudocytidine derivatives for the
9:48 － 10:00
selective recognition of CG base pairs in triple-helix DNA○王 磊 1, 谷口 陽祐 1, 岡村 秀紀 1, 佐々木 茂貴 1（1九大院薬）– 56 –

Poster Presentation
Saturday, 25 March AM

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

25PA-am064S Expanding the amino acid repertoire of ribosomal polypeptide synthesis by theartificial division of codon boxes
1 1
2
3
東大院理 , 東大院工 , 名大院工）○岩根 由彦 1, 人見 梓 2, 村上 裕 3, 加藤 敬行 1, 後藤 佑樹 1, 菅 裕明 （25PA-am077 Halogenation of Benz[f]indole Derivative towards the Synthesis of Antiglioma
Compounds○ Nyo Mi SWE1, 渡辺 敏子 1（1国際医福大薬）
25PA-am084S Synthesis of 2,3-Benzodiazepine Derivatives for Development of Novel Neuroprotecting
Agents○裴 東弘 1, 高山 亜紀 1, 松谷 裕二 1（1富山大院薬）
25PA-am087 Design and Synthesis of Novel Anti-Alzheimer's Disease Agents Having Furan-fused
Perhydrophenantherene Skeleton○呉 詩慧 1, 杉本 健士 1, 松谷 裕二 1（1富山大院薬）
25PA-am126 Synthesis of Iminosugar C-Glycosides via Mannich-Aminocyclization Reactions○ Lingaiah MARAM1, 田中 富士枝 1（1沖縄科学技術大学院大学）

Saturday, 25 March PM

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

25PA-pm045S Effect of counter base of cytosine on deamination of 3-cyanovinyl-carbazole mediatedphoto-cross-linked cytosine in DNA duplex○ Siddhant SETHI1, Minako OOE1, Sakamoto TAKASHI1, Shigetaka NAKAMURA1,
Kenzo FUJIMOTO1（1北陸先端科学技術大学院大学）
25PA-pm097S Polyalongirin A , a novel skeleton compound from Polyalthia longifolia○郭 佳宜 1, 張 誌益 1, 林 昀生 2（1台灣屏東科技大學 , 2台灣美和科技大學）

Saturday, 25 March AM

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

25PB-am035

Simulation time necessary for diminishing the dependency of protein structures on the
crystal condition○斉 非 1, 米田 友貴 1, 根矢 三郎 1, 星野 忠次 1（1千葉大院薬）
25PB-am100 CFH in hippocampus and VTA of CPP rats may be associated with METH addiction○许 嘉旻 1, 赵 欣 1, 孙 懿 1, 蒲 小平 1（1北京大学 药学院）25PB-am189 Active bufadienolide compounds induce G2/M phase arrest  in human glioblastoma cellline U-87
1 1
2
東京薬大薬 応用生化 , 中国中医科学院 中薬研究所）○韓 玲玉 2,1, 袁 博 1, 林 秀樹 1, 辺 宝林 2, 高木 教夫 （25PB-am194S The Downregulation of the Energy Metabolism by Brain Metastatic Melanoma Cell
Derived Exosomes in Human Brain Capillary Endothelial Cell Line; hCMEC/D3○陳 瓊芳 1,2, 内田 康雄 2, 黒田 広樹 2, 梅津 美奈 2, 八木 悠太 2, 立川 正憲 2, 寺崎 哲也 2（1ハイデル
2

ベルグ大医 , 東北大院薬）

Saturday, 25 March PM
25PB-pm085
25PB-pm086

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

Eudebeiolide B inhibits osteoclasto genesis and prevents ovariectomy-induced bone loss
by regulating RANKL-induced calcium signaling○李 承在 1（1韓國生命工学研究院）
Study of the UV Light Conversion of Feruloyl Amides from Portulaca oleracea andTheir Inhibitory Effect on IL-6-Induced STAT3 Activation○李 勝雄 1（1韓国生命工学研究院）– 57 –

25PB-pm087
25PB-pm088
25PB-pm089
25PB-pm090

Inhibitory effects of IL-6-induced STAT3 activation of bio-activecompounds derived
from Salvia plebeia R.Br○魯 文喆 1（1韓国生命工学研究院）
Eudesmane-type sesquiterpenoids from Salvia plebeia inhibit IL-6-induced STAT3
activation○張 賢在 1（1韓国生命工学研究院）
Evaluation for antitumor response and immune activity of Phytochemicals from
Zingiber officinale  Roscoe
Minji SOHN1, Jehyung LEE1, ○ Yongkyu LEE1（1Bio-Science & Engineering, Dongseo University）
Chemical constituents and anti-inflammatory activity of the aerial parts of Curcuma
longa○李 雨松 1（1韓国生命工学研究院）

Sunday, 26 March AM
26PA-am032

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

Chemical Studies on the Ghanaian Plant Thonningia sanguinea Vahl (Part 1)
Ama K. THOMFORD1,2, Reda F. A. ABDELHAMEED1,3, ○山田 耕史 1（1長崎大院医歯薬 ,226PA-am085

3

Department of Biomedical and Forensic Sciences, University of Cape Coast, Faculty of Pharmacy, Suez Canal
University）

Jiao-Tai-Pill and Cinnamaldehyde Alleviates Metabolic Disorder in SHR/NDmcr-cp
Rats○高 明 1, 張 露 2,1, 根岸 裕子 1, 劉 銅華 2, 孫 文 2, 池田 克巳 1（1武庫川女大薬 , 2北京中医薬大）26PA-am116 Screening study on TRAIL-resistance overcoming activity from Celtis tetrandra andAmonum villosum
Prapairat SEEPHONKAI1,2, 荒井 緑 1, 石川 直樹 1, 小谷野 喬 3, Thaworn KOWITHAYAKORN4,○石橋 正己 1（1千葉大院薬 , 2マハサラカン大学理 , 3テムコ , 4コンケン大農）
26PA-am123S Characterization of proanthocyanidin oligomers of Ephedra sinica○ Joanna Justimbaste OREJOLA1, Yosuke MATSUO1, Yoshinori SAITO1, Takashi TANAKA1
1（ Grad. Sch. Biomed. Sci., Nagasaki Univ.）

Sunday, 26 March PM
26PA-pm020

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

The peel constituents and anti-inflammatory activities of Citrus grandis
Ping-Chung KUO1, Hsin-Yi HUNG1, Chia-Wei CHUANG1, Tsong-Long HWANG2,
Young-Ji SHIAO3, ○ Tian-Shung WU1（1School of Pharmacy, National Cheng Kung University Hospital,
2

26PA-pm021

College of Medicine, National Cheng Kung University, School of Traditional Chinese Medicine, Chang Gung
3
University, National Research Institute of Chinese Medicine, Ministry of Health and Welfare）

Anti-Inflammatory Constituents Isolated from Solid-State Fermented Antrodia cinnamomea
Mycelium
I-Chuan YEN1, Shih-Yu LEE2, ○ Li-Shian SHI3（1Graduate Institute of Medical Science, National Defense
226PA-pm022

Medical Center, Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center,3
Department of Biotechnology, National Formosa University）

Components isolated from Cinnamomum kanehirae with growth promotion effects on
Antrodia cinnamomea○ Lih-Geeng CHEN1, I-Hung SHEN1（1Department of Microbiology, Immunology and Biopharmaceuticals,

26PA-pm023

National Chiayi University）

Hypoglycemic Constituents from the Pericarps of Trapa natants L.
○ Hui-Chi HUANG1, Chien-Liang CHAO2, Chih-Hua CHAO3,4, Yueh-Hsiung KUO1（1Department
2of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Herbal Medicine
3
4
R & D Department, Sinphar Pharmaceutical Co., Ltd., School of Pharmacy, China Medical University, Chinese
Medicine Research and Development Center, China Medical University Hospital）– 58 –

26PA-pm024

Multiple Activities of Punica granatum Linne against Acne Vulgaris○ Chia-Jung LEE1, Lih-Geeng CHEN2, Wen-Li LIANG3, Ching-Chiung WANG1,3,4
1

26PA-pm025（ PhD Program for Clinical Drug Discovery of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical
2
University, Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National
3
4
Chiayi University, School of Pharmacy, College of Pharmacy, Taipei Medical University, Orthopedics ResearchCenter, Taipei Medical University Hospital）

New Bafilomycins Produced by a Streptomyces sp. Isolated from a Marine Sponge
Theonella sp.
Yu-Hsin CHEN1,2, ○ Ping-Jyun SUNG2,3（1Department of Life Science and Graduate Institute of2

26PA-pm026

3

Biotechnology, National Dong Hwa University, National Museum of Marine Biology and Aquarium, Graduate
Institute of Marine Biology, National Dong Hwa University）

The Constituents from the Stems of Cissus assamica○ Yu-Yi CHAN1, Chiu-Yuan WANG1, Tian-Shung WU2（1Department of Biotechnology, Southern
226PA-pm027

Taiwan University of Science and Technology, School of Pharmacy, National Cheng Kung University）

Synthesis and biological evaluation of chalcone, dihydrochalcone, and 1,3-diarylpropane
analogues as anti-inflammatory agents○ Hsin-Yi HUNG1, Mopur Vijaya Bhaskar REDDY1, Ping-Chung KUO1, Guan-Jhong HUANG2,
Tian-Shung WU1（1School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National
2

26PA-pm028

Cheng Kung University, School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of
Pharmacy, China Medical University）

Development of dual inhibitors of HDAC 6 and β-amyloid (Aβ) aggregation○ Chun-Yung CHEN1, Cheng-Chung YEN1, Wei-Jan HUANG1,2（1Graduate Institute of2

26PA-pm031

Pharmacognosy, Taipei Medical University, Ph.D Program for the Clinical Drug Discovery from Botanical Herbs,
Taipei Medical University）

Cadinane-Type Sesquiterpenes from Chamaecyparis obtusa and Their Antiausterity
Activity○ Dya Fita DIBWE1, 上田 純也 2, 松本 欣三 1, Suresh AWALE1（1Institute of Natural Medicine,2

University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan., Faculty of Pharmaceutical Sciences, Hiroshima
International University, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.）

26PA-pm032S Chemical Constituents of Citrus hystrix and Their Antiausterity Activity against the
PANC-1 Human Pancreatic Cancer Cell Line○孫 思嘉 1, Dya Fita DIBWE1, Ampai PHRUTIVORAPONGKUL2, Suresh AWALE1
1

26PA-pm057

2（ Institute of Natural Medicine, University of Toyama, Japan, Faculty of Pharmacy, Chiang Mai University,
Thailand）

Chemical Compositions from Cultured Products of the Culinary-Medicinal Honey
Mushroom, Armillaria mellea○ Kun-Ching CHENG1, Young-Ji SHIAO2, Tsong-Long HWANG3, Tian-Shung WU4（1Taiwan
226PA-pm058

Sugar Research Institute, Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine,
34
Graduate Institute of Natural Products, Chang Gung University, School of Pharmacy, National Cheng Kung
University）

Secondary Metabolites and Biological Activities from the Soft Coral Sinularia flexibilis○ Jyh-Horng SHEU1,2,3, Chia-Hua WU1, Tzu-Zin HUANG1, Tsong-Long HWANG4（1Department
226PA-pm059

of Marine Biotechnology and Resources, National Sun Yat-sen University, Graduate Institute of Natural Products,
3
Kaohsiung Medical University, Frontier Center for Ocean Science and Technology, National Sun Yat-sen University,
4
Graduate Institute of Natural Products, College of Medicine, Chang Gung University）

Flaccidoxide-13-acetate, extracted from the cultured soft coral Sinularia gibberosa ,reduces the cell migration and invasion of human bladder cancer through reducing theactivation FAK/PI3K/AKT/mTOR signaling pathways
Guo-Fong DAI1, ○ Yu-Jen WU2（1Graduate Institute of Biotechnology, National Pingtung University of2

26PA-pm060

Science and Technology, Department of Biological Science and Technology, Meiho University）

Scalarane Ssesterterpenes from a Marine Sponge Hippospongia sp. and Their
Anticancer Activity○ Jui-Hsin SU1,2, Yu-Cheng CHEN1,2, Mei-Chin LU1,2（1Graduate Institute of Marine Biology, National
2

Dong Hwa University, National Museum of Marine Biology and Aquarium）– 59 –

26PA-pm061

Four new Sesquarterpenes (C35), Cryptoterpenes A-D, from the bark of Cryptomeria
japonica○ Yueh-Hsiung KUO1, Hui-Chi HUANG1, Cheng-Chi CHEN2, Chi-I CHANG3（1Department of2

26PA-pm106

Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Department of3
Chemistry, National Taiwan University, Department of Biological Science and Technology, National Pingtung
University of Science and Tchenology）

The synergistic effect of magnesium and static magnetic field on enhancing theosteogenesis of dental pulp stem cell
○ Yu-Xuan HUANG1, Kuen-Yu HUANG1, Wei-Zhen LEW2, Haw-Ming HUANG2（1Graduate
226PA-pm107

Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, School of Dentistry, College ofOral Medicine, Taipei Medical University）

Histomorphometric and transcriptome evaluation of early healing bone treated with anovel human particulate dentin powder○ Yu-Chih HUANG1, Haw-Ming HUANG2（1School of Dentistry, College of Oral Medicine, Taipei Medical
226PA-pm108

University, Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University）

Prescribing patterns of Wu Lin San alleviates Cyclophosphamide-induced rat
hemorrhagic cystitis○ Jia-Feng XU1, Steven Kuan-Hua HUAN2, Ching-Chiung WANG1（1School of Pharmacy, College of2

26PA-pm109

Pharmacy, Taipei Medical University, Division of Urology, Department of Surgery, Chi Mei Medical Center）

High turnover rate of baicalin, a suitable marker substance from Scutellaria
baicalensis in Huang-Chin-Tang○ Li-Ying HUANG1, Li-Geeng CHEN3, Chia-Jung LEE2, Chua-Jung CHANG4,
Ching-Chiung WANG1,2,4（1Graduate Institute of Pharmacognosy, Taipei Medical University, 2Clinical Drug
3

26PA-pm110

26PA-pm111

Discovery from Botanical Herbs, Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi
4
University, School of Pharmacy, Taipei Medical University）

Fabrication of magnesium ion release membrane using carboxymethyl cellulosehyaluronic acid
○ Chia-Jen NIEN1, Hsin-Pei CHIANG1, Kuen-Yu HUANG1, Yu-Chih HUANG2, Haw-Ming
HUANG1（1Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, 2Schoolof Dentistry, College of Oral Medicine, Taipei Medical University）

Fabrication and mechanical property test of biodegradable PLLA-embeddedmagnesium bone screw○ Guan-Wei ZHANG1, Yu-Chih HUANG2, Haw-Ming HUANG1（1Graduate Institute of Biomedical
226PA-pm112

Materials and Tissue Engineering, Taipei Medical University, School of Dentistry, College of Oral Medicine, Taipei
Medical University）

The correlation with Ge Gen Tang pattern and common cold: the retrospective study○ Pei-Ying CHOU1,2, Chen-Jei TAI1,2, Shu-Chen CHIEN3, Ching-Chiung WANG1,3（1Graduate
226PA-pm113

Institute of Pharmacognosy, Taipei Medical University, Department of Traditional Chinese Medicine, Taipei Medical
3
University Hospital, School of Pharmacy, College of Pharmacy, Taipei Medical University）

Prescribing Patterns of Ban-Xia-Xie-Xin-Tang alleviate ethanol-induced rat gastricmucosa cell damage○ Pin-Chen HUANG1,2, Tsung-Hsiu WU1,2, Ching-Chiung WANG1,3（1Graduate Institute of2

26PA-pm114

3

Pharmacognosy, Taipei Medical University, Department of pharmacy, Taipei City Hospital, School of Pharmacy,
College of pharmacy, Taipei Medical University）

Chemopreventive effects of Kuei Pi Tang on Oxaliplatin-induced neuropathy in rats
Shih-Han CHEN1, Chia-Jung CHANG1, Her-Shyong SHIAH2, ○ Ching-Chiung WANG1,3（1School2

26PA-pm115

3

of Pharmacy, Taipei Medical University, Internal Medicine, Oncology, Taipei Medical University Hospital, Graduate
Institute of Pharmacognosy, Taipei Medical University）

The Evaluation of Biological Activity of Kai-Lan Extract○ Daih-Huang KUO1, Shu-Yu LI1, Chun-Yann LEE1, I-Li CHEN1, Yi-Jen TSAI1,
Kuo-Cheng WANG1（1Graduate Institute of Pharmaceutical Technology, Tajen University）– 60 –

Sunday, 26 March AM
26PB-am199
26PB-am293

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

English Role-play Using Visual Aids to Enhance Patient Comprehension○池上 小湖 1, 西村 真澄 1, フォン フーワー 1（1京都薬大）Learning Pharmaceutical Dispensing with Role-Plays○ Foo Wah FOONG1, 池上 小湖 1, 西村 真澄 2（1京都薬大 , 2兵庫県立大）Sunday, 26 March PM
26PB-pm027

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

Effect of dietary restriction from old on the levels of Akt1 and mTOR in rat liver○ Keiko ODERA1, Yi SHANG2, Ramesh SHARMA3, Shizuko KAKINUMA2,
Yoshiya SHIMADA2, Ryoya TAKAHASHI1（1Fac. of Pharm. Sci., Toho Univ., 2Dept. of Radiation Effects
3

26PB-pm146

Research, NIRS, QST, Dept. of Biochem., North-Eastern Hill Univ.）

Cost Analysis for Treatment of Adult Patient in Universal Coverage Healthcare
in Systemic Lupus Erythematosus and Lupus Nephritis in Fiscal Year 2013 at
Srinagarind Hospital, Khon Kaen University, Thailand○ Theera RITTIROD1, Jananya TANABOON1, Phattranit KAMTUO1,
Nungruthai SOOKSAI1, Siraphop SUWANNAROJ2（1Faculty of Pharmaceutical Sciences, Khon Kaen
2

University, Faculty of Medicine Khon Kaen University）

Monday, 27 March AM

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

27PA-am014S A MALDI-TOF mass spectroscopy-based approach to evaluate the cytosolictranslocation efficiency of  octaarginine-mediated intracellular protein delivery○ Jan Vincent ARAFILES1, 川口 祥正 1, Bechara CHERINE2, Illien FRANCOISE2, 河野 健一 1,
Burlina FABIENNE2, Sagan SANDRINE2, 二木 史朗 1（1京大化研 , 2パリ第６大学）
27PA-am015 Anticancer mechanism of action of palmitoyl piperidinopiperidine○安藤 さえこ 1, 松本 晴年 1, 深町 勝巳 1, 二口 充 1, 酒々井 眞澄 1（1名市大院医）
27PA-am032 Design and Screening of an o -Substituted Anilide Library for Histone Lysine
Demethylase Inhibitors○ Pattaporn JAIKHAN1, 伊藤 幸裕 1, 鈴木 孝禎 1（1京府医大院医）
27PA-am099 Chemical constituents derive from Artocarpus xanthocarpus and their antimelanogenesis mechanism investigation○柯 宏慧 1, 金 語菁 1, 陳 益昇 1（1高雄醫科大 - 高雄醫學大學香粧品學系）
27PA-am135 Learning status of pharmacists belonging to the Ai-Gi (Aichi-Gifu) Block of MIC Co.,
Ltd. (Second Survey Report)○森 厚司 1, 山本 有人 1, 山田 隆博 2（1株式会社ミック 岐阜支店 , 2株式会社ミック 名古屋北支店）

Monday, 27 March PM
27PA-pm117

Room PA (Sendai International Center Conference Bldg 2F)【Sakura】

Cadmium-incduced autophagy through JNK and Ca2+ in rat mesangial cells○藤代 瞳 1,2, Douglas M. TEMPLETON1（1Department of Laboratory Medicine and Pathobiology,
2

University of Toronto, 徳島文理大学薬）

Monday, 27 March AM
27PB-am017

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

Optimization for Neural Catecholamines, its metabolites and Related Drugs in a Single
LC-MS/MS Analysis using API4000○ Andrea Roxanne Jocsing ANAS1,2, 鈴木 弘美 1, 今西 進 2, 原田 健一 2,3, 澤田 誠 1（1名古屋大学環23

境医学研究所 , 名城大学薬学部 , 名城大学大学院総合学術研究科）

27PB-am030S Screening of chemical modifications in human skin keratins using on-tape digestion
method○川瀬 士瑛 1, 廣嶋 佑亮 1, 大江 知行 1, 李 宣和 1（1東北大院薬）– 61 –

27PB-am031S Stable isotope dilution LC/ESI-SRM/MS method for N-terminal pyruvamide
angiotensin peptides in human plasma○池田 真人 1, 横田 涼 1, 大江 知行 1, 李 宣和 1（1東北大院薬）
27PB-am093 Paraoxon induces tremor by activating nicotinic acetylcholine receptors in mice
○アルベス伊波 イーゴル 1, 國澤 直史 1, 清水 佐紀 1, 尾西 美咲 1, 野村 有治 1, 松原 菜美 1,
岩井 千紘 1, 小川 瑞葵 1, 橋村 舞 1, 河合 悦子 1, 大野 行弘 1（1大阪薬大・薬品作用解析）
27PB-am098 Induction of epileptiform activity and drug responses  in cultured human iPSC-derived
neuronal networks using MEA system○小田原 あおい 1,2,3, 鈴木 郁郎 2（1東北大学 , 2東北工業大学 , 3特別研究員）

Monday, 27 March PM
27PB-pm166

Room PB (Sendai International Center Exhibition Bldg 1F)【Exhibition Hall】

Microemulsion formulation optimization for topical application○吴 宝珠 1, Yu-Hsiang LIN1（1高雄医大）– 62 –

2. Abstracts
SL-2

Designed Probes for Measuring and Controlling DNA Damage Repair

Eric KOOL

Stanford University

Despite exciting progress made recently in precision medicine, several common cancers remaindifficult to treat, including lung, colorectal, and pancreatic cancer, which together account for over
200,000 deaths annually in the U.S. A common molecular factor in many of these tumors is highlevels of reactive oxygen species (ROS), which leads to oxidative damage in DNA. This frequently
results in the formation of 8-oxoguanine (8-OG), which is both toxic and mutagenic. To cope with thisdamage, tumor cells evolve strategies to support rapid growth, and thus often misregulate the enzymes
that combat this damage. Two important cases are MTH1 and OGG1, which remove 8-OG from thenucleotide pool and from DNA itself. We hypothesize that developing approaches to measure andcontrol the activities of these enzymes will provide new and promising strategies for controlling tumor
growth. However, until very recently it has been difﬁcult to measure or alter these enzymesʼ activities.
Here I describe the design of novel and sensitive chemical probes that act as luminescence reportersof the cellular activities of multiple DNA damage surveillance pathways, including MTH1 and
OGG1. With collaborators we have used these probes to identify new small-molecule modulators ofthese pathways, some of the ﬁrst in their class. We are using the information learned to develop new
hypotheses regarding how modulating the activities of these pathways via small molecules can provide
biologically important mechanistic data, and potentially clinically useful outcomes, in cancer.
Our aims are to develop new probes to quantify speciﬁc repair activities in tumor cells and tissues;
to identify and develop new small-molecule modulators of the enzymes; and to test novel biologicalhypotheses regarding how altering repair activity may suppress tumor growth. We hope that our new
molecular tools will be useful to the cancer research community as a whole. Moreover, if successful,our work may lead to new targeted strategies for cancer treatment, and to practical methods forevaluating patients for these therapies.

– 63 –

SL-5

Genotypic Variability and the Quantitative Proteotype

Ruedi AEBERSOLDETH Zurich / University of Zurich

The question how genetic variability is translated into phenotypes is fundamental in biology andmedicine. Powerful genomic technologies now determine genetic variability at a genomic level andat unprecedented speed, accuracy and (low) cost. Concurrently, life style monitoring devices andimproved clinical diagnostic procedures generate an even larger amount of phenotypic information.
To date, the effects of genomic variability on the expressed information of the cell, and thus on thephenotype, have been mainly studied by transcript profiling. Yet, most biochemical activities arecatalysed by proteins.
We are therefore aiming at the systematic determination of the effects of genomic variability on theproteotype (the acute state of the proteome of a cell). This is becoming feasible due to the developmentof new mass spectrometric methods, exemplified by SWATH-MS, that generate highly reproducible
proteome maps from samples of (large) cohorts (1).
In this presentation we will discuss the current state of the computational and quantitative aspects of
SWATH-MS. We will additionally talk about selected applications of the technology using genetic
reference strain and cell line compendia, to determine the effect of genetic variability on the quantitative
proteome, thus functionally connecting the genome, the proteome, and complex phenotypes (2,3,4).
1.

Gillet LC, Navarro P, Tate S, Roest H, Selevsek N, Reiter L, Bonner R, Aebersold R. (2012)
Targeted data extraction of the MS/MS spectra generated by data independent acquisition:a new concept for consistent and accurate proteome analysis (2012). Mol Cell Proteomics
11:O111.016717.

2.

Picotti P, Clément-Ziza M, Lam H, Campbell DS, Schmidt A, Deutsch EW, Röst H, Sun Z,
Rinner O, Reiter L, Shen Q, Michaelson JJ, Frei A, Alberti S, Kusebauch U, Wollscheid B,
Moritz RL, Beyer A, Aebersold R. (2013) A complete mass-spectrometric map of the yeast
proteome applied to quantitative analysis. Nature. 494(7436):266-70.

3.

Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference
population (2014). Wu Y, Williams EG, Dubuis S, Mottis A, Jovaisaite V, Houten SM, Argmann
CA, Faridi P, Wolski W, Kutalik Z, Zamboni N, Auwerx J, Aebersold R. Cell. 158(6):1415-30.
doi: 10.1016/j.cell.2014.07.039.

4.

Williams EG, Wu Y, Jha P, Dubuis S, Blattmann P, Argmann CA, Houten SM, Amariuta T,
Wolski W, Zamboni N, Aebersold R, Auwerx J.(2016) Systems proteomics of liver mitochondria
function. Science 10;352(6291):aad0189.

– 64 –

SL-6

The Functionalization of C-H Bonds

Christina WHITE

University of Illinois

Classically, the practice of chemical synthesis has focused on building hydrocarbon scaffolds while
concurrently introducing oxygen, nitrogen, and carbon functionality. We have discovered andcommercialized palladium/sulfoxide catalysts for allylic C-H functionalizations, iron(PDP) catalysts
for aliphatic C-H hydroxylations, and manganese phthalocynine catalysts for intramolecular C(sp3)-H
aminations. These catalysts proceed with unprecedented levels of reactivity and tunable selectivities incomplex molecule settings, without the need for directing groups. We have delineated site-selectivity
rules based on the physical organic properties of C-H bonds (electronic, steric, and stereoelectronic)
that have proven general across a variety of aliphatic C-H functionalization reactions. Using these noveltransition metal catalysts we have validated late stage C-H oxidation, i.e. direct introduction of oxidized
functionality into C(sp3)-H bonds of molecule scaffolds, as a powerful approach for streamlining
synthetic sequences and directly diversifying natural products, including complex peptides. This lecture
aims to provide an overview of these areas in addition to current advances in chemoselective andasymmetric C-H oxidations.

– 65 –

SL-7

Evolution of Orbitrap mass spectrometry and its future perspectives

Alexander MAKAROV
Thermo Fisher Scientiﬁc

This talk presents ﬁrst-hand a short but eventful history of Orbitrap mass spectrometry, from laying
down the first principles to its current status as the leading mass spectrometric technique for highresolution, high mass accuracy quantitative analysis.
Originating from an ideal (and therefore never realized) Kingdon trap, this analyzer can provide highperformance analytical characteristics only when it is highly integrated with the ion injection process.
The advent of pulsed injection from an external ion storage device allowed the Orbitrap analyzer toenter mainstream mass spectrometry, initially as a part of a hybrid instrument. Since its introduction theutility of the Orbitrap has been extended by coupling with additional capabilities such as higher-energy
dissociation (HCD), ETD, FAIMS, UVPD, ion mobility and different ionization techniques such as
MALDI, in-vacuum EI/CI, APPI, etc.
The widespread adoption and use of Orbitrap mass spectrometry has been driven by its characteristic
ability to acquire high-resolution, high mass accuracy data for qualitative and quantitative analysis.
Increasing speed of chromatographic separations imposes ever increasing requirements on throughput
of mass spectrometric analysis and demand higher spectral acquisition rates, improved spectral quality
and better control of different ion optical devices within mass spectrometers.
Recent improvements in these directions are exempliﬁed for Q Exactive and Orbitrap Fusion families
of instruments, with numerous new modes of operation enabled by parallelization of detection and ion
processing and concerted operation of different ion-optical devices. A special emphasis is made ontechnical solutions that allow quantitative analysis in these instruments, despite Orbitrap analyzer beingof an ion trapping type.
It is shown that quantitative analysis in Orbitrap mass spectrometry is now highly feasible due to aunique combination of high space charge capacity of the C-trap, improved control over the number ofstored ions, intelligent ﬁlling and high sensitivity with built-in high mass accuracy, resolving powerand dynamic range of analyzer. New modes of data-independent, targeted and top-down acquisition are
overviewed.
In conclusion, future trends and perspectives of Orbitrap mass spectrometry are discussed, including
its inroads into emerging areas of mass spectrometric analysis, such as analysis of intact proteinsand protein complexes under native conditions, e.g. antibody-drug conjugates and antibody-antigen
complexes. It is shown that Orbitrap-based mass spectrometers possess compelling potential as an(ultra-) high resolution platform not only for high-end proteomic applications but also for screening,
trace and targeted analysis and clinical analysis by LC/ and GC/MS.

– 66 –

OS23-1

Complexity Generation in Fungal Natural Product Biosynthesis - New Enzymatic
Reactions○ Yi TANG1
1

Department of Chemical and Biomolecular Engineering and Department of Chemistry and Biochemistry,
University of California, Los Angeles

Nature performs challenging synthetic transformations using powerful enzymes. These enzymes
are frequently found in the biosynthetic pathways of natural products, many of which have served as
inspirations for generations of synthetic chemists over the last ﬁfty years. With recent advances in ourabilities to manipulate the biosynthetic pathways, many powerful enzymes have been revealed andcharacterized. In this talk, I will present a selection of recent work in the identiﬁcation, characterizationand engineering of several enzymes that catalyze difficult transformations and generate structuralcomplexity in fungi. Examples include multifunctional P450s, Diels Alderases and enzymes thatcatalyze epoxide rearrangements will be covered.

OS23-2

Redesigning Complex Natural Products Biosynthesis○ Ikuro ABE1
1

The Univ. Tokyo, Grad. Sch. Pharm. Sci.

Meroterpenoids are hybrid natural products that are partially derived from terpenoid origin, and thosefrom fungi exhibit an extremely wide range of structural diversity and biological activities. Recent
advances in genome sequencing technologies and development of tools for biosynthetic studies haveallowed the discovery of many biosynthetic gene clusters for fungal meroterpenoids and intensive
researches at genetic and enzymatic level. We have been working on the meroterpenoids derived
from a simple aromatic precursor, 3,5-dimethylorsellinic acid (DMOA), and discovered several
fascinating enzymes that catalyze drastic structural rearrangement which dramatically increase
structural complexity of the molecules. For example, multifunctional, nonheme iron-dependent
dioxygenases are the key components in the austinol and the anditomin pathway, in which the enzymes
are responsible for the construction of the spiro-lactone and the bicyclo[2.2.2]octane core, respectively.
On the other hand, the terretonin biosynthesis involves a cytochrome P450 and an isomerase, which
work collaboratively to perform the unprecedented ring expansion reaction to afford the terretonin
scaffold. This presentation will focus on our recent advances in redesigning complex natural products
biosynthesis.

– 67 –

OS23-3

The Creation of New Functional Molecules by Rational Design at Protein-Protein
Interface of Fatty Acid Synthase and Polyketide Synthase○ Shiou-Chuan (Sheryl) TSAI1
1

Departments of Chemistry, Molecular Biology and Biochemistry, and Pharmaceutical Sciences, University ofCalifornia, Irvine

Polyketides, non-ribosomal peptides, and fatty acids are complex molecules biosynthesized by large
enzyme complexes called polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), andfatty acid synthase (FAS), respectively. These large enzyme complexes consists of 10 – 100+ enzyme
domains and biosynthesized a speciﬁc product by a highly choreographed transportation of building
blocks among the enzyme domains. How protein-protein interactions in PKS, NRPS and FAS help
convey product speciﬁcity remains largely a mystery, and the lack of such knowledge has hampered
rational design of complex molecules via mega-synthase engineering. Presented herein is our recent
progress in the structural and functional studies of a trans-acyltransferase PKS-NRPS and FAS that
focus on the engineering of protein-protein interface to promote new complex molecule formation.
Data of X-ray crystallographic structures, protein NMR, molecular dynamic simulation, in vitro and invivo assay results are presented to provide a high resolution and dynamic picture of mega-synthases inaction.

OS23-4

Phytochemical Genomics: A Basis for Redesign of Plant Natural Products
Biosynthesis○ Kazuki SAITO1,2
1

Chiba Univ., Grad. Sch. Pharm. Sci., 2RIKEN CSRS

Phytochemical genomics is a recently emerging sector in plant science, which elucidates the genomic
basis of the biosynthesis and the function of plant metabolites. Phytochemical genomics is a basis forredesign of plant natural products, which are estimated to reach 200,000 or 1,000,000 compounds.
Phytochemical genomics has been mostly advanced in Arabidopsis thaliana , a model plant for plant
genomics, by means of combination of genomics, transcriptomics and metabolomics. Recently, anumber of similar investigations in medicinal plants have been carried out to discover the genes and themetabolic networks for the biosynthesis of bioactive plant specialized metabolites. In this presentation,
I will discuss a general perspective on phytochemical genomics from A. thaliana to medicinal plants
and its application in the research program of redesign of natural products biosynthesis.

– 68 –

OS33

FIP forum 2017: International educational trends for pharmaceutical researchers
in the next generation
Masaru KATO1
1

Univ. Tokyo, Grad. Sch. Pharm. Sci.

Many new drugs have been developed by constant efforts, passion and wisdom of many pharmaceuticalresearchers and many diseases have been overcome by these drugs. For the right usage of the drug, it isessential to have cooperation of many people concerned, such as pharmaceutical researcher, pharmacist,and patient. Furthermore, international harmonization and cooperation is progressing. Trends andfuture prospects of pharmaceutical education in the United States, South Korea, Japan and Australia
are introduced in this forum. Through these presentations, we would like to discuss the direction ofpharmaceutical education that is responsible for future pharmaceutical research from basic to clinicalresearches.

OS33-1

Pharmacy education in the US, a hint for reevaluating the Japanese system○ Tomohiko OHWADA1, Erika S. CHAN1,2
1

Univ. Tokyo, Grad. Sch. Pharm. Sci., 2Rutgers Univ., School of Pharmacy

One of the authors came to recognize the signiﬁcant differences in pharmacy school education between
in the US and in Japan, as well as the differences in the professional careers and responsibilities ofpharmacists in the two nations. Although herein shown is one example of the pharmacy school in theUS, which may have its own limitation, it shall shine the light in reevaluating the pharmacy school
education, particularly medicinal chemistry, in Japan. The decisive difference between the pharmacy
educations in the two nations is a 6 years undergraduate program in Japan, whereas it is a 4+4 years
Doctor of Pharmacy (Pharm D) professional degree program in the US. Prospective candidates are
accepted into the US pharmacy schools after completing the 4 years of undergraduate study, and theyreceive the graduate school level education from the ﬁrst professional year of the four-year program.
The Pharm D (Doctor of Pharmacy) degree awarded to pharmacy students is a professional degree,which is different from the widely known PhD degree. Among the 132 pharmacy schools in the US,
about 90% of those schools requires a total of 8 years of education before their graduates become
qualified as pharmacists, and, as exceptions, 7 schools with long history offer a 6 year combined
program (2 years undergraduate + 4 years professional), which permits enrollments of students directlyfrom high school. Rutgers, the State University of New Jersey, with which one of the authors is
afﬁliated, is one of these 7 schools, and it offers a highly comprehensive study of medicinal chemistry
in the second half of the professional education program.
– 69 –

OS33-2

Pharmacy education in Korea; Challenges for a better future○ Kyungim KIM1
1

Korea Univ., College of Pharm.

In South Korea, pharmacy education has gone through signiﬁcant changes throughout the past decade
to improve competency of pharmacy sector and increase its base in academia. Pharmacy education
system in Korea was changed from a four-year program to a six (2+4) year program in 2009. The 2+4
program is consisted of at least two years of undergraduate program before the entrance to the program
followed by 4 years of pharmacy education for students who have passed the Pharmacy Education
Eligibility Test (PEET). The new education system offers courses that combine scientific, clinical,
and professional approaches in the ﬁeld of pharmacy. Under the new 2+4 system, pharmacy students
are also given more opportunities to practice in various settings than they had before. Six years havepassed after the introduction of new pharmacy education program in Korea, and a number of ongoing
efforts still exist to innovate the system. This presentation will be about the current status of pharmacy
education and our challenges faced in bettering future of pharmacy education in Korea.

OS33-3Current status and perspectives of the 6-year pharmaceutical education:
Aiming to train pharmacist-scientist○ Ken-ichi INUI1,2
1

Professor Emeritus of Kyoto Univ., 2Professor Emeritus of Kyoto Pharmaceutical Univ.

Social needs such as the progress of the separation of dispensing from medical practice, andsophistication and diversiﬁcation in medicine prompted the establishment of a six-year pharmaceuticaleducation, which was inaugurated in April, 2006. We have sent out the sixth cohort of graduates to thesociety in March, 2017. Furthermore, the revised pharmaceutical education model-core-curriculum
emphasizing the outcome-based education has been implemented since April, 2015; this prescribes"10 fundamental competencies required of a pharmacist". Meanwhile, pharmacistsʼ responsibilities
in medical practice have also changed signiﬁcantly. As the interdisciplinary team approach to medicalcare permeates, pharmacists now engage themselves in deeper and wider activities; such as, drug
management in the hospital ward, medication instruction to patients, supporting doctor's prescription
and proposing medication therapies, participating in home health care. The negative aspect of the sixyear pharmaceutical education is a decrease in research power. The practice of balanced education ofscience, art, and humanity, focusing on problem ﬁnding and problem solving type education will lead tothe development of a pharmacist-scientist and a breakthrough development of pharmaceutical research.
The speaker worked at the department of pharmacy, university hospital for 31 years, and then assumed
office as the president of a pharmaceutical university. Based on his background, he will present his
opinion.
– 70 –

OS33-4

Education and workforce development○ William N. CHARMAN1,2
1

Monash Univ., Faculty Pharm. and Pharm. Sci., 2FIP Education Executive Committee

There can be no healthcare without a properly qualiﬁed healthcare workforce. At the FIP education
conference held in Nanjing in November 2016, a global vision and goals to transform pharmaceutical
workforce around the world was discussed and agreed. This presentation will outline these outcomes,
the next steps, and the means for FIP Member Organisations to engage and contribute.

– 71 –OS42

PSJ-PSK Joint Symposium: The mechanism, evaluation, prediction and diagnosisof drug-induced liver injury
Kouichi YOSHINARI1
1

Sch Pharmaceut Sci, Univ Shizuoka

Liver is one of the major target organs of chemical toxicity and drug-induced liver injury (DILI) has
been the major cause of the discontinuation of new drug development and withdrawal of drugs frommarket. Therefore, the establishment of evaluation and prediction systems of DILI and the identiﬁcationof biomarkers of DILI are very advantageous for efﬁcient new drug development and the preventionof adverse drug reactions. In this Japan-Korea joint symposium, the recent advances in the research on
chemical toxicity and DILI will be presented by 4 speakers from The Pharmaceutical Society of Japanand The Pharmaceutical Society of Korea.
Drug-responsive nuclear receptors play critical roles in the liver functions including drug metabolism,
energy metabolism and lipid homeostasis. Thus, the association of nuclear receptors with chemical
toxicity and DILI will be presented. Next, in vitro DILI evaluation system focusing on the formationof reactive metabolites by cytochrome P450s, which is considered as a key initiating step for mostof DILI, will be introduced. Finally, the potential use of microRNA as a novel therapeutic target andbiomarker of DILI will be presented and discussed.

OS42-1

Role of nuclear recptors in drug-induced liver injury○ Kouichi YOSHINARI1
1

Sch Pharmaceut Sci, Univ Shizuoka

Xenobiotic-responsive nuclear receptors (NRs) including PXR, CAR and PPARα play crucial roles
in multiple liver functions such as xenobiotic disposition, energy metabolism and lipid homeostasis.
Thus, the dysfunction of these NRs may lead to liver failure or disease/injury. In addition, the xenobiotic
activation of CAR and PPARα induces hepatocyte proliferation and hepatocarcinogenesis in rodents.
Although PXR and CAR belong to the same subfamily (NR1I) of the NR gene superfamily and sharenumbers of target genes, the association of PXR with hepatocyte proliferation and hepatocarcinogenesis
has remained unclear. We have been thus investigating the role of PXR in the hepatocyte proliferationand hepatocarcinogenesis using in vivo and in vitro models and found a unique role of PXR in
hepatocyte proliferation. Our results show that PXR activation (treatment with a murine PXR ligand
PCN) alone does not induce hepatocyte proliferation but enhances CAR- or PPARα-mediated hepatocyte
proliferation in mice. The mechanistic analyses suggest that PXR activation induces the down-regulationof the cell-cycle suppressor genes. Moreover, we have found that PXR activation stimulates thehepatocyte proliferation during the recovery from liver injury induced by carbon tetrachloride. Thus, it
seems that PXR activation increases hepatocytesʼ susceptibility to proliferating stimuli (e.g. xenobiotics,
injury, growth factors, etc.). In this symposium, I will introduce our recent ﬁnding on the role of PXR in
hepatocyte proliferation and would like to discuss its relevance to humans.

– 72 –

OS42-2

Chemical-induced abnormal lipid metabolism and multiple metabolic toxicities○ Byung-Hoon LEE1
1

College of Pharmacy, Seoul National University, Korea

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism. Inactivation of AMPK
results in the repression of cellular catabolism and activation of several anabolic processes leading to thenegative metabolic adjustment. Suppression of AMPK by chemicals induces multiple metabolic toxicities
in various tissues. Inactivation of AMPK by orotic acid induces hepatic lipogenesis by activating mTORLXRα-SREBP-1 pathway in hepatocytes. In the vasculature, suppression of AMPK induces endothelial
dysfunction. Metformin- or insulin-induced activation of Akt and eNOS is compromised by orotic acidor uric acid in HUVEC cells as well as in rat aortic ring resulting in the endothelial dysfunction andhypertension. AMPK activation, although generally regarded as a positive regulator of various metabolic
syndromes, can also increase the risk of the metabolic syndrome. We found that activation of AMPK by
metformin or berberine induces the phosphorylation of CCAAT/enhancer-binding protein β (C/EBPβ)and the expression of fatty acid translocase/CD36 in the liver. Upregulation of CD36 facilitates the uptakeof fatty acid in the liver and induces hepatic steatosis. Autophagy, a lysosome-mediated intracellular bulk
degradation process, is promoted by AMPK and inhibited by mTOR. Blockage of autophagy by somenon-steroidal anti-inflammatory drugs inhibited breakdown of lipid droplet and induced cellular lipid
accumulation. Taken together, chemical-induced impairment of lipid metabolism disrupts cellular energy
homeostasis and induces diverse metabolic toxicities.

OS42-3

Prediction of metabolism-dependent hepatotoxicity using human liver
microsomes○ Sang Kyum KIM1
1

College Pharm, Chungnam Natl Univ

Drug-induced liver injury (DILI) via metabolic activation by drug-metabolizing enzymes, especiallycytochrome P450 (CYP), is a major cause of drug failure and drug withdrawal. In this study, an in vitro
model using HepG2 cells in combination with human liver microsomes (HLM) was developed forprediction of DILI. The cytotoxicity of cyclophosphamide, a model drug for bioactivation, was augmented
in HepG2 cells cultured with microsomes in a manner dependent on exposure time, microsomal protein
concentration, and NADPH. Experiments using pan- or isoform-selective CYP inhibitors showedthat CYP2B6 and CYP3A4 are responsible for bioactivation of cyclophosphamide. In a metabolite
identification study employing LC-ESI-QTrap and LC-ESI-QTOF, cyclophosphamide metabolites
including phosphoramide mustard, a toxic metabolite, were detected in HepG2 cells cultured withmicrosomes, but not without microsomes. The cytotoxic effects of acetaminophen and diclofenac werealso potentiated by microsomes. The potentiation of acetaminophen cytotoxicity was dependent on CYPdependent metabolism, and the augmentation of diclofenac cytotoxicity was not mediated by either CYPor UDP-glucuronosyltransferase-dependent metabolism. The cytotoxic effects of leﬂunomide, nefazodone,
and bakuchiol were attenuated by microsomes. The detoxication of leflunomide by microsomes was
attributed to mainly CYP3A4-dependent metabolism. The protective effect of microsomes against
nefazodone cytotoxicity was dependent on both CYP-mediated metabolism and nonspecific protein
binding. Nonspecific protein binding but not CYP-dependent metabolism played a critical role in theattenuation of bakuchiol cytotoxicity. The present study suggests that HepG2 cells cultured with HLM canbe a reliable model in which to predict DILI via bioactivation by drug metabolizing enzymes.
– 73 –

OS42-4

Diagnostic and therapeutic potential of miRNAs for liver injury○ Miki NAKAJIMA1
1

Kanazawa Univ. Facl. of Pharm. Sci.

microRNAs are major post-transcriptional factors which negatively regulate gene expression throughtranslational repression or mRNA degradation. To date, over 2,500 miRNAs have been identiﬁed inhuman. microRNAs regulate every aspect of cellular processes, and their dysregulation is associatedwith a variety of diseases; therefore microRNAs are received considerable attention as new therapeutictargets. In addition, since miRNAs stably exist in the body ﬂuids, miRNAs has a potential as a new
biomarker of various diseases.
Liver injuries are caused by various factors, and are classified into multiple types. Conventional
serum biomarkers for liver injury unfortunately cannot distinguish different types of liver injury. In
addition, their levels are increased in patients without liver injury. To overcome the problems, weinvestigated the potential of plasma miRNA as biomarker of liver injury. Using mouse models, wefound that plasma miRNAs could be sensitive and specific biomarkers of liver injury. In addition,
proﬁling of several selected plasma miRNA in patients could distinguish different types of liver injury.
Retinoid X receptor α (RXRα), one of the nuclear receptors, has protective role for liver fibrosis.
We found that human RXRα is regulated by miR-34a. In the livers with ﬁbrosis, miR-34a level wasincreased, and RXRα level was decreased. When we administered anti-miR-34 to mouse model withliver ﬁbrosis, mitigation of liver ﬁbrosis was observed. In this symposium, diagnostic and therapeuticpotential of miRNAs for liver injury is discussed.

– 74 –

S14-1

Identiﬁcation of Novel Diels Alderases from Fungal Biosynthetic Pathways

Masao OHASHI1, Kenji WATANABE1, Ken HOUK2, ○ Yi TANG2
1

University of Shizuoka, 2UCLA

Diels Alder cycloaddition is an important reaction for construction of multicyclic compounds with
efﬁciency and stereocontrol. In recent years, several enzymes that can catalyze the Diels Alder reaction
in bacterial natural product biosynthetic pathways have been identified. However, no biochemical
conﬁrmation of Diels Alderase activities has been demonstrated for fungal pathways, despite the wide
occurrence of natural products that are proposed to derive from such cyclizations. In this talk, wewill discuss the discovery and characterization of two new Diels Alderases from fungal polyketidebiosynthetic pathways. Both genetic and biochemical reconstitution were performed on both enzymes
to demonstrate the reactions that are catalyzed. The implication of the discoveries on genome mining ofother polycyclic natural products will also be discovered.

S31-4

The unique pharmacology of synapses in the outer retina○ Steve H. DEVRIES1
1

Northwestern University Feinberg School of Medicine

Unique among CNS circuits, the outer retina uses analog signals to process the physiological stimulus,
light. To deal with small, slowly ﬂuctuating signals, outer retinal synapses use specialized mechanisms
with unusual pharmacology. The cone photoreceptor synapse is both a critical link in the pathway forsignaling across the retina and a site for parallel processing. Each cone contacts 12-13 bipolar cell types
that fall into two functional classes, ON and OFF. My lab focuses on the kainate receptors that mediate
glutamatergic transmission between cones and the 5 OFF bipolar cell types. Unlike AMPA receptors,
which recover sensitivity rapidly following a glutamate pulse, kainate receptors strongly desensitize
and slowly recover (t=0.5-5 s). In the cone dominant ground squirrel retina, the OFF bipolar cell types
use 2-3 different types of kainate receptors. Receptors differ with respect to glutamate afﬁnity (0.35
versus ~3 mM), recovery rate after an agonist pulse (t =1.5-2.0 s versus 0.5 s), and spatial distribution.
Surprisingly, molecular evidence indicates that the GluK1 receptor subunit predominates, and thatfunctional diversity might result from coexpression of GluK3, GluK5, and/or NETO1. Together,receptor type and contact organization enable the OFF bipolar cell types to transmit cone signals overdifferent intensity ranges.

– 75 –

S54-4

Screening of lipid hydroperoxide-mediated protein modiﬁcation using stable
isotope labeling by fatty acids in cell culture (SILFAC) coupled with isotope
pattern dependent scan
○ Seon Hwa LEE1, Ryo TAKAHASHI1, Tomoyuki OE1
1

Tohoku Univ. Grad. Sch. of Pharm. Sci.

[Introduction] Lipid hydroperoxide-mediated modifications to proteins have recently gained more
attention because of their possible involvement in various degenerative diseases. Lipid hydroperoxides
can be formed via reactive oxygen species- or enzyme-mediated oxidation of polyunsaturated fatty
acids. The hydroperoxides can decompose to generate α,β-unsaturated aldehydes such as 4-oxo-2(E )nonenal and 4-hydroxy-2(E )-nonenal, which are involved in the regulation of inﬂammation and cellularsignaling through modiﬁcation of amino acid residues of signaling kinases. In the present study, wedeveloped the metabolic labeling (stable isotope labeling by fatty acids in cell culture: SILFAC) andMS-based proteomic methodology that enables global screening of lipid hydroperoxide-mediatedprotein modiﬁcation.
[Methods] MCF-7 cells were cultured with [13C18]-LA-albumin. LA-containing major phospholipids
were monitored for the cells to produce a 1:1 ratio of LA and [13C18]-LA. The cells were then subjectedto oxidative stress and proteins were analyzed using the developed proteomic methodology after an
enzymatic digestion.
[Results & Discussion] Global screening using SILFAC and isotope pattern dependent scan identiﬁed the
major lipid hydroperoxide-mediated modiﬁcations to proteins in MCF-7 cells. The current global proteomic
strategy can be applied to uncover novel biomarkers for lipid peroxidation in various cell systems.

– 76 –

25F-pm08S

Tetrandrine potentiates the glucocorticoid efficacy via P-glycoprotein and MAPK
inhibition in mitogen-activated human peripheral blood mononuclear cells○許 文成 1,2, 孟 科含 1, 塗 遠超 2, 田中 祥子 1, 恩田 健二 1, 杉山 健太郎 1, 平野 俊彦 1,
山田 陽城 1（1東京薬大薬 , 2湖北省中医病院薬）[Purpose] Glucocorticoids (GC) play significant roles in treatments of inflammatory andautoimmune diseases. However some patients show a poor or absent response to use GC.
The purpose of this study was to explore whether tetrandrine (TET) combined with GC
could be a new treatment strategy to resolve GC resistance.
[Methods and Results] Human peripheral blood mononuclear cells (PBMCs) was chosen
as a model to study the synergic effect of TET with methylprednisolone (MPSL),
including the underlying action mechanisms. TET decreased the IC50 value of MPSL
significantly, but it showed little toxic effect on the concanavalin A-activated PBMCs.
Both TET and MPSL inhibited the secretion of pro-inflammatory cytokines TNFα andIL-6 significantly and the synergic inhibitory effect could be observed. TET and/or MPSL
did not increase the percentage of CD4+ CD25+ Foxp3+ regulatory T cells in CD4+ T cells.
However TET with or without MPSL significantly inhibited the function of drug efflux
pump P-glycoprotein 170 (P-gp) of CD4+, CD8+ T cells and lymphocytes. TET suppressed
the phosphorylation of MAPK and this effect was potentiated by MPSL. These TET
effects were suggested to be beneficial for improving the immunosuppressive efficacy of
GC. GC combined with TET could be a new therapeutic approach to resolve
GC-resistance via inhibiting the function of P-gp and blocking MAPK signaling pathway
but not affecting on CD4+ CD25+ Foxp3+ regulatory cells.

25H-pm16

Controlled delivery of insulin by liposome within thermoreversible hydrogel
after subcutaneous administration○楊 智鈞 1, 呂 愛平 1, 趙 中振 1, 陳 暁昱 1（1香港浸会大学中医薬学院）[aim] This study was to develop an in situ gel system comprising insulin-containing
liposomes dispersed within the thermoreversible gel for controlled drug release andimproved diabetic treatment efficiency after subcutaneous administration of one single
dose.
[methods] Insulin was encapsulated into liposomes by the vesicular phospholipid gel
technique and the thermoreversible gel was prepared. In vitro release of insulin from theliposomal gel and other formulations was studied using the dialysis membrane method.
The in vivo absorption and bioactivity of insulin released from the liposomal gel and otherformulations were studied in a streptozotocin-induced diabetic rat model. The amount of
insulin released in vivo was quantified using the enzyme-linked immunosorbent assay(ELISA), and its bioactivity was determined by its ability to reduce the blood glucose
levels in diabetic rats. Furthermore, the in vivo biocompatibility of the PF127 gel-based
delivery systems with and without liposomes was studied based upon the histology of rat
skin tissue samples collected at the site of injection.
[results] Insulin was loaded into liposomes 89%. The liposomal gel had the longest
drug-release period. The liposomal gel could release insulin into the bloodstream for up to
7 days and significantly enhance drug bioavailability as compared to liposomes or PF127
gel alone, with reduction in blood glucose levels for up to 4 days. With no inflammatory
response observed in the rat skin tissue, the liposomal gel delivery system demonstrated
excellent biocompatibility in vivo.
[conclusion] The results indicate that insulin-containing liposomes dispersed within the
PF127 gel can be used as an alternative to the conventional daily insulin therapy

25P-am02S

Study of reaction between 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) andtertiary amines by LC-MS○ Xiaomin LI1, Yayoi KANBAYASHI2, Zekun YANG1, Muneki ISOKAWA1,
Chao WANG1,3, Takashi FUNATSU1, Masanobu UCHIYAMA1,3, Makoto
TSUNODA1（1Graduate School of Pharmaceutical Sciences, The University ofTokyo, 2Institute of Innovation, Ajinomoto Co., Inc., 3Riken）[Introduction] 4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), a pre-labeling reagent
for HPLC analysis, has high reactivity to amines under mild conditions. Therefore, it has
been widely used for analysis of amino acids and biogenic amines. It is generally believedthat NBD-F is not reactive towards tertiary amines. However, as for the
NBD-derivatization of ɛ-N, N-dimethyl-lysine (diMeLys) with both primary and tertiaryamino groups, its di-NBD-derivative was obtained, indicating that tertiary amino group in
diMeLys may be reactive to NBD-F. To reveal generality of reactivity between NBD-F
and tertiary amines, reaction of several tertiary amines including diMeLys with NBD-F
was investigated.
[Methods] Tertiary amines were reacted with NBD-F in alkaline borate buffer at 60 ºC.
The reaction solutions were analyzed by reversed-phase HPLC with fluorescence (ex. 470
nm, em. 530 nm) and ESI-MS detection.
[Results and Discussion] First, LC-MS analysis showed that NBD-F could react with
diMeLys to form two products (mono- and di-NBD-diMeLys, m/z 338 and 501,
respectively). The structure of di-NBD-diMeLys was investigated by LC-MS/MS. The
fragmentation pattern indicated that two NBD moieties in di-NBD-diMeLys were boundto primary and tertiary amino group of diMeLys, respectively. Next, the formation of
di-NBD-diMeLys from the reaction of mono-NBD-diMeLys with NBD-F was confirmed.
Finally, reaction of other tertiary amines with NBD-F was investigated by
LC-fluorescence-MS. Although no significant fluorescence signal was observed from
NBD-derivatives of the tertiary amines studied, molecular weights corresponding to these
NBD-derivatives were found by LC-MS analysis. It can be concluded that NBD-F reacts
with tertiary amines and the derivatives basically have no fluorescence.

25P-am08S

LC/ESI-MS approach for characterization of Angiotensin II-induced lipid
peroxidation in human endothelial cells○藤岡 修平 1, 髙橋 亮 1, 大江 知行 1, 李 宣和 1（1東北大院薬）【 Objective 】 Angiotensin (Ang) II (DRVYIHPF) has been implicated in various
cardiovascular diseases. Ang II stimulates the generation of reactive oxygen species (ROS)
that mediates cardiovascular remodeling. ROS can also induce lipid peroxidation withproduction of the genotoxic aldehydes, 4-oxo-2(E)-nonenal (ONE) and
4-hydroxy-2(E)-nonenal (HNE). However, there has been little attention given to the lipidhydroperoxide-derived damage to cardiovascular systems. Our previous studies havedemonstrated that ONE and HNE modified N-terminus, Arg2 and His6 of Ang II and thesemodifications altered the biological activities of Ang II. The goal of the present study is todetect lipid-derived modifications to Ang II, glutathione (GSH) and proteins in the cellstimulated by Ang II to clarify how lipid peroxidation modulates cardiovascular system.
【Methods】EA.hy926 cells, the human vascular endothelial cell lines, were employedbecause of their expression of Ang II type 1 receptor (AT1R) and good sensitivity to Ang II
stimulation. To detect extremely low-abundant modified-Ang IIs, -GSH and -proteins,conditions for clean-up and LC/ESI-SRM/MS were optimized. The cells were incubatedwith Ang II in the presence of ascorbic acid (AscA) and CuSO4 at 37 °C for 24 h.
【Results & Discussion】Ang P (ONE-modified Ang II) and [His6(HNE)]-Ang II weredetected in the cell culture medium incubated with Ang II, and further increased in thepresence of AscA and CuSO4. A dose-dependent increase in TOG (ONE-modified GSH)
was also observed upon treatment with Ang II. Losartan (AT1R blocker) was shown to
inhibit the formation of TOG in a dose-dependent manner, supporting Ang II-induced lipid
peroxidation and modification of various cellular molecules. Detection of lipid
modified-proteins that are involved in cardiovascular system will improve understandingof the role that lipid peroxidation plays in cardiovascular diseases.

25R-pm15

What does a complete quantum mechanical binding analysis of dipeptidyl
peptidase IV with antidiabetic drugs conclude?
○ Arulmozhiraja SUNDARAM1,2, Naoya MATSUO1, Seiji OKAZAKI1,2, Hitoshi SHIMANO3,4,
Hiroaki TOKIWA1,2,4（1Department of Chemistry, Rikkyo University, 2Research Center for
Smart Molecules, Rikkyo University, 3Department of Internal Medicine (Endocrinology andMetabolism), University of Tsukuba, 4AMED-CREST）
Incretin hormones consisting of glucagon-like peptide and glucose-dependent
insulinotropic polypeptide stimulate the insulin secretion and suppress glucagon secretion.
This mechanism, rather than insulin and its secretalogues, is now well tolerated therapeuticroute for the treatment of type 2 diabetes. Since incretins are naturally cleaved andinactivated by dipeptidyl peptidase IV (DPP-4), DPP-4 inhibitor that activates incretin
actions is the current blockbuster medicine to deal chronic type 2 diabetes. Recently westudied the interaction between DPP-4 and four of its inhibitor drugs (sitagliptin,
linagliptin, alogliptin, and teneligliptin) quantitatively by using fragment molecular orbital(FMO) calculations. Apart from quantifying the interactions between the drugs and theamino acid residues of the DPP-4, the study explained the superior inhibitory activities oflinagliptin and teneligliptin.1 Continuation of this work, the present study aimed toinvestigate the interaction between DPP-4 and its two new DPP-4 inhibitor drugs,
trelagliptin and omarigliptin, by using quantum mechanical FMO method at correlated
RI-MP2/cc-pVDZ level of theory. By calculating the interfragment interaction energies
between all the amino acid residues and the inhibitor drugs, a complete insight, nature andthe strength, of the interaction is investigated. Using quantum mechanics/molecularmechanics (QM/MM) hybrid calculations, the total binding energies of the all six inhibitor
drugs towards the DPP-4 are obtained, which are related to the resultant biological potencyof the inhibitor as measured experimentally in a biological assay. By combining all theseresults with those of the previous study,1 some comprehensive and crucial conclusions are
made regarding the potential DPP-4 inhibitor drugs.
1
Arulmozhiraja, S.; Matsuo, N.; Ishitsubo, E.; Okazaki, S.; Shimano, H.; Tokiwa, H.
PLoS ONE 2016, 11, e0166275-1-15.

25T-pm04

Organocatalytic Asymmetric Desymmetrization of Alkane-1,n-Bisphenols
via Aromatic Bromination: Enantiotopic Group Differentiation of Distal
Bisphenols○ Harisadhan GHOSH1, 川端 猛夫 1（1京大化研）[Purpose] To develop a method for asymmetric desymmetrization of alkane-1,n-bisphenols
based on organocatalytic aromatic bromination.
[Results] Asymmetric brominations of bisphenol 1 (n=1) with N-bromosuccinimide (NBS)
in chloroform at -20 oC in the presence of 20 mol% of organocatalyst 3(1) followed by
DMAP catalyzed acetylation gave monobrominated product 2a in 62% yield and 79% ee.
Asymmetric desymmetrization of distal 1,5-bisphenol 1 (n=2) took place with moderate
selectivity and low yield (2b, 25% yield, 66% ee). On the other hand, bromination of
two-carbon-longer analogue 1 (n=3) furnished 2c in an almost racemic form. Mechanistic
aspects for the remote asymmetric bromination will be discussed.

Reference:(1) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem.
Soc. 2007, 129, 12890.

– 77 –

25T-pm11

25V-pm07[Background and purpose]
Our previous work showed that deoxyfluorinative rearrangement reactions of
4,4-disubstituted 2-hydroxycyclohexa-2,5-dieneones 1, derived from catechols, under
different conditions, always gave 3 as a major product along with our desired product2.1) These products were thought to be generated by the fluorination of the carbonylgroup of 1 to give an intermediate A followed by the immediate migration of the aryl
moiety in an SN2’ manner. This study aims to find a solution for the regioselective
rearrangement to obtain 2 in better yields and to examine its substrate generality.
[Methods, results and conclusion]
Our first trial was to examine steric and electronic effects of the substituent R1 on theregioselectivity; however, it did not work to make full control. Our next approach via
the acid-catalyzed defluorinative rearrangement reaction of difluorinated products 4,
obtained from 1, produced a mixture of 2 and 3. After intensive trials, 2 (X-Y = CHCH2,
R1 = CO2Me) was obtained in a quantitative yield from the nonafluorobutanesulfonate 5(X-Y = CHCH2, R1 = CO2Me) via acid treatment. Applicability of this method to someother 5 with different X, Y, and R1 will be discussed.

Aim: Lysophosphatidic acid (LPA), one of the simplest phospholipids, exerts various
patho- and physiological functions through its six GPCRs (LPA1~LPA6). LPA signaling
regulates angiogenesis, embryo implantation, pulmonary fibrosis and many other aspects.
In the recent study, we found LPA was produced in mouse CLP sepsis model, so LPA may
play an important role in immunity. In order to figure out the mechanism, we used a
simple sepsis model induced by LPS to investigate the effect of LPA.
Method: Systemic sepsis was induced in mice by lipopolysaccharide (LPS) administration(1mg/kg, intraperitoneally). LPA, lysophosphatidyl choline (LPC), lysophosphatidyl
ethanolamine (LPE) and LPA3 agonist T13 were also injected intraperitoneally. ELISA
was used to measure plasma cytokine level.
Result: Firstly, by IL-10 ELISA, we found LPA induced much higher IL-10 level thanother lysophospholipids such as LPE and LPC. So in order to figure out which LPA
receptor is related in LPA-induced IL-10 production, we tried with LPA receptor agonist.
T13, one LPA3 agonist was applied first. T13 can also induced dramatically high level of
IL-10 production. The increased IL-10 that induced by low-dose T13 (500mM) could be
reduced in LPA3 KO mice. However, the effect of high-dose T13 (5mM) could not.
Considering that T13 can also activate other LPA receptors except its strong LPA3 affinity,
it is possible that LPA3 only contribute partially to T13-induced IL-10 production. So, inthe near future, other LPA receptors that are related and physiological functions of
LPA-induced IL-10 are the major subjects that need to be investigated.

Regiocontrol of the deoxyfluorinative rearrangement reactions of
4,4-disubstituted 2-hydroxycyclohexa-2,5-dieneones into ortho-fluorophenols○ Ahmed ABUBAKR1, 斉藤 和幸 1, 田窪 景太 1, 赤井 周司 1（1大阪大学大学院薬学研究科）

Lysophosphatidic acid promotes IL-10 expression in a mouse LPS model○王 嬌 1, 可野 邦行 1, 佐竹 響子 1, 青木 淳賢 1（1東北大院薬）

Ref. 1) Keita Takubo, Shuji Akai et al., Eur. J. Org. Chem. 2016, 1562-1576.

25T-pm16

25W-pm05

The Pd-catalyzed reactions have very high impact on organic synthesis, medicinal
chemistry and pharmaceutical industry. For the stabilization of Pd, bimetallization has
attracted much attention because of their enhanced catalytic properties based on the
combined action of two or more chemically different metals. Recently, we found that theactivity and stability of Pd nanoclusters (NCs) can be enhanced by bimetallization with Au
and PVP stabilized such bimetallic NCs showed unique activity for carbon-chlorine bondactivation in Ullmann coupling and hydrodechlorination reaction. However, the polymer
bound quasi-homogenous Pd-catalysts often suffers from instability despite of higher
activity due to weak interaction with stabilizer. Developing heterogeneous catalysts forhomogenous reaction not only increase the stability and recyclability but also lead todifferent catalytic activity and selectivity. The strength of the metal-support interactions is
considerably influence the stability and catalytic properties. So, in this work, we preparedhighly active palladium nanoclusters stabilized on hydrotalcite (Pd-HT) by chemical
reduction method. The catalyst worked
efficiently for carbon halogen bondactivation in Suzuki coupling reaction andarylation of indoles under mild condition.
In addition, Pd-HT showed high efficiency
for reduction of nitro arenes to amines
under atmospheric pressure of H2. Further,thepreparationofheterogeneous
bimetallic catalysts and testing theircatalytic activity is underway.

Background and Purpose: The primitive streak in peri-implantation embryos forms themesoderm and endoderm and controls cell differentiation. The metabolic cues regulating
primitive streak formation remain largely unknown.
Methods: 1. Mouse embryonic stem (ES) cell differentiation system and a library ofwell-characterized drugs were used to identify these metabolic factors. 2. Using
metabolomics and pharmacologic approaches we identified the downstream signaling
pathway of mevalonate. 3. Tagging-via-substrate approach was used to find the target
protein farnesylated by mevalonate pathway.
Results: 1. Statins, which inhibit the mevalonate metabolic pathway, suppressed primitive
streak formation in vitro and in vivo. 2. Primitive streak formation requires protein
farnesylation but not cholesterol synthesis. 3. Nuclear lamin B1 and small G proteins were
farnesylated in embryoid bodies and important for primitive streak gene expression.
Conclusion: Protein farnesylation driven by the mevalonate pathway is a metabolic cue
essential for primitive streak formation.

25U-pm03

25W-pm09S[Introduction] The aldol reaction is one of the most powerful and versatile methods for theconstruction of carbon-carbon bonds in a stereoselective manner.1 It provides anatom-economic approach to β-hydroxyl carbonyls, which constitute a large family ofchiral intermediates for the synthesis of biologically active compounds and natural
products.2 In order to meet the continuous demand of enantioenriched propionate units
with β-stereogenic centers, we focused on the direct catalytic asymmetric aldol reaction
using a propionamide without an electron-withdrawing group at the α-position. With afine-tuning of catalytic conditions, the direct catalytic asymmetric aldol reaction of
7-azaindoline amide proceeded in a highly stereoselective manner.
[Results] The reaction of 7-azaindoline amide 1 with aldehydes in the presence of 10
mol% catalyst comprising of mesitylcopper/chiral bisphosphine ligands gave thecorresponding aldol adducts. The use of different type of ligands enabled the reactions ofynals and aromatic aldehydes.

In pulmonary fibrosis (PF), normal tissue is replaced by scar tissue, causing tissue
dysfunction. The scar tissue is mainly composed of myofibroblasts differentiated fromfibroblasts. It is known that transforming growth factor-β1 (TGFβ1) plays a central role inthis mechanism. Myofibroblasts express α-smooth muscle actin (αSMA), collagens,fibronectin and so on, so they are widely used as markers of fibrosis. Nintedanib,
pirfenidon and anti-inflammatory drugs such as steroids and immunosuppressants(cyclosporin A (CsA), FK506, cyclophosphamide and azathioprine) are now used fortreatment. However, the detailed effects of these drugs are still unclear since many types ofcells are involved in the disease progression. We first investigated the effects of thesedrugs on αSMA expression in human lung fibroblasts. Among the drugs, only CsA showedanti-fibrotic effects induced by TGFβ1. We investigated the mechanism of the effects of
CsA, and focused on hypoxia-inducible factor 1α (HIF1α). HIF1α is a subunit of HIF, atranscriptional factor, and is usually degraded in normoxia. On the other hand, in hypoxia,
it remains stable. As like previous reports, we confirmed that TGFβ1 increased HIF1α
expression while CsA decreased. In addition, inhibiting HIF1α expression by an inhibitorand siRNA, succeeded to decrease αSMA expression induced by TGFβ1. Our results
indicated that HIF1α would be a novel therapeutic target of pulmonary fibrosis. Moreover,CsA decreased the already-induced expression of αSMA and fibronectin in
myofibroblasts-like cells from an PF patient. In vivo experiments, we could show that
intratracheal (i.t.) administration of CsA significantly decrease αSMA and HIF1α
expressions induced by bleomycin. These data suggested that CsA would be more
effective for treatment for PF when it used as inhaler than oral/systemic administration.

Activation and stabilization of Pd nanoclusters for reaction under milder
conditions○ Sangita KARANJIT1, 柏原 雅也 1, 中山 淳 1, 難波 康祐 1（1徳島大薬）

Direct Catalytic Asymmetric Aldol Reaction of Amides○ Zijian LIU1, Toshifumi TAKEUCHI1, Roman Krzysztof PLUTA1,
Fernando Arteaga ARTEAGA1, Naoya KUMAGAI1, Masakatsu SHIBASAKI1（1微生物化学研究所）[1] Modern Aldol Reactions, Vols. 1&2 (Ed.: R. Mahrwald), Wiley-VCH, Berlin, 2004.
[2] Zhang, Y.; Farrants, H.; Li, X. Chem. Asian J. 2014, 9, 1752.

The mevalonate pathway regulates primitive streak formation via protein
farnesylation○虞 若星 1, 岡本 ‐ 内田 好海 1, 仁科 博史 1（1東京医歯大学難治研）

Investigation of anti-fibrotic effects of cyclosporin A in pulmonary fibrosis○山崎 璃沙 1, 粕谷 善俊 2, 藤田 哲雄 2,3, 梅澤 弘毅 2,3, 柳原 まどか 1, 中村 浩之 1,
吉野 一郎 4, 巽 浩一郎 3, 村山 俊彦 1（1千葉大院薬・薬効薬理 , 2千葉大院医・分子生体制御 , 3千葉大院医・呼内 , 4千葉大院医・呼外）– 78 –

25W-pm13S

Expression of NEAT1 is significantly higher in MCPyV-positive Merkel cell
carcinoma than MCPyV-negative one.
○秋月 源 1, 今村 亮俊 2, 山田 俊理 3, 水谷 玲奈 3, 松下 倫子 1, 長田 桂子 1, 桑本 聡 1,
加藤 雅子 1, 秋光 信佳 3, 林 一彦 1（1鳥取大医 , 2千葉大薬 , 3東京大薬）
OBJECTIVES:
Merkel cell polyomavirus (MCPyV) is monoclonally integrated into about 80% of Merkel
cell carcinoma (MCC), an aggressive neuroendocrine skin cancer. In this study, weinvestigated the involvement of NEAT1, a nuclear long noncoding RNA participating in
the immune-regulation upon viral infection, in the MCC.
METHOD and RESULTS:
We firstly quantified expression of NEAT1 and SFPQ, a transcript factor, in
MCPyV-positive and -negative MCCs by RT-qPCR and FISH. NEAT1 expression level
was upregulated at almost two times in MCPyV-positive MCC comparing with
MCPyV-negative one (P<0.05). Paraspeckle numbers of MCPyV-positive and -negative
MCCs were approximately 2:1. 15 genes including immune-related genes overlapped
among two microarray profiles of MCPyV-related or NEAT1-regulated genes.
CONCLUSIONS:
Our findings suggest that NEAT1 regulates some genes including immune-related genes in
MCPyV-positive MCCs by forming more number of paraspeckle. This is the first report of
NEAT1 expression which may play as an actual regulator of genes in MCC.

26F-am08

Quassinoids: Viral Protein R Inhibitors from Picrasma javanica Bark
Collected in Myanmar○ Nwet Nwet WIN1,2, Takuya ITO1, Takeshi KODAMA1, Yi Yi WIN2, Hla NGWE2,
Hiroyuki MORITA1（1Division of Natural Products Chemistry, Institute of Natural Medicine,
University of Toyama, 2Department of Chemistry, University of Yangon, Myanmar）[Purpose] Myanmar is a tropical country with a rich source of medicinal plants and local people havebeen used them in the traditional medicine since time immemorial. Although Picrasma javanica bark has
been used for the treatment of cancer, diabetes, malaria and AIDS for a long time, the chemical
constituents and biological activities have not been explored yet. This study focused on the isolation of
secondary metabolites and evaluation of their inhibitory effects on Viral protein R (Vpr) of humanimmuno deficiency virus.
[Methods and Results] The chemical constituentswere isolated from the chloroform extract of P.
javanica bark using combination of various
chromatographic methods. The structures of all theisolates were elucidated on the basis ofspectroscopic analyses. The isolation ofchloroform soluble extract of P. javanica afforded
thirteen new quassinoids, picrajavanicins AM(113), together with three known analogues,
javanicins B (14), F (14), and I (16). The absoluteconfiguration at C-4 of picrajavanicin L (12) was
determined to be S by the modified Mosher method.
The anti-Vpr activities of picrajavanicins AK(111), and M (13), and javanicins B (14), F (15),and I (16) were evaluated against TREx-HeLa-Vpr
cells and their structure-activity relationships(SAR) were studied. Among the tested compounds,
javanicin I (16) exhibited the most potent anti-Vpr
activity with 2.5 M in comparing with that of thepositive control, damnacanthal.

The effects of arsenic disulfide alone and combined with tetrandrine on
viabilities of 2D- and 3D-cultured MCF-7 breast cancer cells○趙 玉雪 1,2, 恩田 健二 1, 田中 祥子 1, 袁 博 3, 清海 杏奈 4, 大野 保奈美 1, 植松 南美 1,
杉山 健太郎 1, 平野 俊彦 1（1東京薬科大学薬学部臨床薬理学教室 , 2中国中医科学
院鍼灸研究所 , 3東京薬科大学薬学部応用生化学教室 , 4東京薬科大学薬学部医薬品安全管理学教室）
Objective: The aim of the present study was to investigate the effects of arsenic disulfide(As2S2) on two-dimensional (2D) and three-dimensional (3D) culture model of MCF-7 cellline. The synergistic effect of tetrandrine was also investigated. Methods: Cell viability
was evaluated by CCK-8 assay. A series of different concentrations of As2S2 was applied
alone or combined with fixed concentration of tetrandrine (3µg/ml and 5µg/ml). Drugsensitivities of 3D-cultured MCF-7 cells to different concentrations of As2S2 alone, As2S2
combined with 3µg/ml tetrandrine, or As2S2 combined with 5µg/ml tetrandrine, wereanalyzed and compared with those of 2D-cultured model. Results: The inhibitory effect of
As2S2 on 2D-cultured MCF-7 cells was in a time- and dose-dependent manner. Comparedwith 2D-cultured cells, MCF-7 cells in 3D culture showed increased drug resistance. The
IC50 values of As2S2 alone, As2S2 combined with 3µg/ml tetrandrine, and As2S2 combinedwith 5µg/ml tetrandrine were all increased significantly in 3D-culture compared with thosein 2D-culture. The combination of As2S2 and tetrandrine elevates the efficacy of the former
to decrease cell viability in both 2D- and 3D-cultured MCF-7 cells. Conclusion: Ourfindings suggest that As2S2 has an inhibitory effect on cell viability in 2D-cultured MCF-7
cells. In contrast, MCF-7 cells in 3D-culture showed drug resistance. Tetrandrine canpromote As2S2 induced inhibitory effects in both 2D- and 3D-cultured MCF-7 cells.

26Q-am03

26Q-am04

New diterpenoids from Plectranthus scutellarioides collected in Indonesia○ Kartika SENDA1, Takuya ITO1, Hiroyuki MORITA1（1富山大学和漢研）[Purpose]
Plectranthus scutellarioides belongs to the family Lamiaceae and widely distributed
throughout Asia and Australia. It has been used as traditional folk medicine in Indonesia
for treatment of hemorrhoids, dyspepsia, skin diseases, and eye inflammation. However,studies of the chemical constituents and biological activity of this plant species have notbeen extensively investigated. In our course of search for new bioactive constituents fromIndonesian medicinal plants, phytochemical study on P. scutellarioides was carried out.
[Results and Discussion]
The CHCl3 extract of the P. scutellarioides leaves was subjected to MPLC over silica
gel to obtain fractions. Purification by preparative TLC and HPLC led to the isolation of
two new abietane-type diterpenoids. The chemical structures of isolated compounds were
elucidated by careful analyses of spectroscopic data including NMR and HREIMS.
Cytotoxic and antibacterial activities of isolated compounds are currently underinvestigation.

Key words: MCF-7 cell line, two-dimensional culture, three-dimensional culture, drug
resistance, As2S2, tetrandrine

26P-am07S

Development of stealth shell based on polycarboxybetaine structure tuned to
selectively interact with cells in tumor extracellular acidic pH○ Abdul-Hackam RANNEH1, 武本 宏泰 1, 野本 貴大 1, 松井 誠 1, 友田 敬士郎 1,
西山 伸宏 1（1東工大院化生研）【Purpose and Methods】Polycarboxybetaines (PCBs) are in a class of polymers that havestable hydration layer as a result of strong electrostatic interaction with water. Thishydration property suppresses nonspecific interactions of PCBs with biomacromoleculesin blood, providing PCBs-coated nanoparticles (NPs) with prolonged blood circulation
time, toward efficient accumulation in tumor based on enhanced permeation and retention
effect. Meanwhile, extracellular pH in tumor tissue is weakly acidic (pH~6.5), comparedto blood and normal tissue, due to tumor-specific metabolic activity (i.e., Warburg effect).
This acidic condition in tumor motivates us to design a PCB with pH-responsiveness, andthus we developed poly-L-glutamide (PGlu) with side chains having a carboxyethyl unit
and one aminoethylene unit (EDA-Car) or two repeated aminoethylene units (DET-Car).
PGlu(DET-Car) potentially behaves as polycation selectively in acidic tumor environment,
leading to interaction with anionic extracellular matrix (ECM). In this study, fluorescencecorrelation spectroscopic (FCS) analysis and flow cytometric analysis (FCM) were
performed to investigate the pH-responsive interaction of Cy3-PCBs with heparin (one of
the components of ECM) and A549 (human lung carcinoma) cells, respectively.
【Results and Discussion】In FCS analysis, PGlu(DET-Car) interacted with heparinselectively at acidic pH (<6.5); the hydrodynamic diameter of PGlu(DET-Car) derivative
increased by 20% compared to its original value. In addition, PGlu(EDA-Car) showed
negligible interaction with heparin in the treated pH range (5.0-8.0), confirming the acidic
pH-responsive behavior of PGlu(DET-Car). Moreover, results in FCM analysis showed
acidic pH-responsive cellular uptake of PGlu(DET-Car) for cultured A549 cells. The cells
treated with PGlu(DET-Car) at pH 7.4 showed comparable Cy3 fluorescence intensitywith the cells treated with PGlu(EDA-Car) and non-treated cells, whereas 2-fold increasein the intensity was observed for the cells treated at pH 6.5, suggesting the interaction of
PGlu(DET-Car) with ECM in tumor acidic pH for enhanced cellular uptake.

26Q-am12S

Synthesis of the glycosyl fattyacids for Mincle-ligand obtained from thepathogenic fungus Malassezia○ Huy LE VAN1, 田中 千晶 1, 山﨑 晶 2, 宮本 智文 1（1九大院薬 , 2九大生医研）
Purpose: Mincle (macrophage inducible C-type lectin), function as pattern recognition
receptor and plays a central role in immunity to fungal pathogens. In 2013, we identified
an unique mannosyl fatty acid linked to mannitol (#44-2) as a Mincle ligand from alipophilic component of the pathogenic fungus Malassezia1). To investigate the function
and mode of actions of #44-2, we synthesized the mimics of 10-O-β-mannosyl stearicacid.
Results: Six derivatives, 12-O- α- or β- glycosyl (mannose, glucose,galactose)-stearicacid were synthesized together with 12-O-[β-mannosyl (1→2)-β-mannopyranosyl]-stearicacid. In this presentation, the syntheses and Mincle
ligand-activity will be discussed.

1) T. Ishikawa, T. Miyamoto, S. Yamasaki, et al., Cell Host Microbe, 13, 477 (2013).

– 79 –

26Q-pm03

26T-pm13[Aim] Astragalus mongholicus is a well-known medicinal plant used to treat general
weakness, chronic illness, swelling and phlegm; it also exhibits anti-inflammation
properties and improves physical energy and strength. This study evaluated PPARαmRNA expression in female and male reproductive systems, and provided an insight into
the crosstalk between ERα and PPARα transcription pathways in uterus by hot water
extract of A. mongholicus root (AsR) administration.
[Material and method] Female and male 12-week-old mice were divided into three groups,
and administrated a free access to chow, AsR-, and bezafibrate-supplements for 56 days
(the females) and 74 days (the males). Changes in body and organs weight were evaluated,
and PPARα mRNA expression levels, estradiol in serum and ERα levels in uterus were
determined.
[Results and conclusion] AsR influenced a significant increase in PPARα mRNA
expression levels in the ovary and uterus (the females), but not in the testis (the males). It
showed AsR is more effective on females than males. ERα levels in the uterus also
decreased (p<0.05). Moreover, decreases in uterine weights were also observed after AsR
treatment (p<0.01). Therefore, these findings suggest that A. mongolicus root might be a
growth inhibition of uterine leiomyoma due to increase of PPARα mRNA expression
levels in the uterus.

C-Glycosides are valuable building blocks for the synthesis of a variety of
biologically important natural products. Synthesis of C-glycosides, however, usuallyrequires laborious protection-deprotection processes. We present here a Cu(I)-catalyzed
diastereoselective C-glycosidation reaction to incorporate ketones into unprotectedpyranoses1.
The concept of hard anion-conjugated soft metal catalysis was the basis for ourreaction design2. The aldol reaction between ketone-derived Cu(I) enolates and thealdehyde form of sugars, both generated by the CuOR Brønsted base catalyst (generated
from mesitylcopper and substrates) 3 was a key for the successful C-glycosidation process.
Our original achiral bidentate phosphine ligand with a large bite angle was essential for thehigh reactivity. Products were obtained in high yield and diastereoselectivity for thereactions of unprotected aldoses with various ketones. Studies toward extending the utilityof the methodology to other sugars and synthesis of natural products on the basis of thisprotecting group-free catalytic C–C bond-formation are now in progress.

PPARα expression influences on atrophy of the mouse uterus by Astragalus
mongholicus root - treatment○ Banzragchgarav ORKHON1, Kyoko KOBAYASHI1, Batkhuu JAVZAN2,
Sasaki KENROH1（1東北医薬大 , 2モンゴル国立大学）

Copper(I)-Catalyzed Dehydrative C-Glycosidation of Unprotected Pyranoses
with Ketones○謝 瀟葦 1, 魏 暁峰 1, 施 世良 2, 清水 洋平 1, 金井 求 1（1東大院薬 , 2中国科学院上海有機化学研究所）(1) X.-F. Wei, S.-L. Shi, X.-W. Xie, Y. Shimizu, M. Kanai, ACS Catal. 6, 6718-6722 (2016)(2) M. Kanai, S. Matsunaga, K. Oisaki, Y. Shimizu, J. Synth. Org. Chem. Jpn. 2013, 71, 433(3) S.-L. Shi, X.-F Wei, Y. Shimizu, M. Kanai, J. Am. Chem. Soc. 2012, 134, 17019

26R-pm06

26U-am01

Development of Near-Infrared Photoactivatable Oxygenation Catalyst
Targeting Amyloid- β○倪 積智 1,2, 谷口 敦彦 1,2,3, 小澤 柊太 1, 堀 由起子 1, 富田 泰輔 1, 國信 洋一郎 1,2,
相馬 洋平 1,2, 金井 求 1,2（1東大院薬 , 2JST-ERATO, 3東京薬大薬）

Direct Catalytic Asymmetric Mannich-Type Reaction of α -Chlorinated andBrominated Amides○孫 博 1, Pandur Venkatesan BALAJI1, 熊谷 直哉 1, 柴崎 正勝 1（1微化研）
Haloamines are versatile intermediates for synthesis of natural products andpharmaceuticals. Conventional methods for enantioselective access to haloamines usually
involve activation of multiple bonds with halonium ion sources.1 The use of readily
available chlorinated or brominated pronucleophiles in Mannich-type reactions offer analternative methodology affording this class of compounds, while limited examples havebeen reported to date.2
α-Chloro and bromo 7-azaindolinylamide as latent enolates were examined for the
directed catalytic asymmetric Mannich-type reactions, anticipating that α-chloro or bromo
amides display sufficient stability without undesired substitution and elimination reactions.
These reactions showed excellent reactivity with both aromatic and aliphatic imines, andunique selectivity profile was observed for multi-substituted aromatic imines. The
important building blocks of α-chloro-β-amino acid and chlorinated amino alcohol weredecently obtained by direct hydrolysis and reduction of 7-azaindolinylamide moiety.

Aim: Amyloid protein aggregation is generally toxic and intimately related to a number ofhuman diseases. Amyloid-β protein (designated Aβ), related to Alzheimer’s disease, is therepresentative example. Because protein aggregation generally depends on intermolecularhydrophobic interactions, covalent installation of hydrophilic oxygen atoms to a protein(i.e., oxygenation) would decrease the aggregative property via stabilizing hydrated
states.1,2
Method: We embarked on the transformation utilizing aerobic oxygen and light as oxygen
atom and energy sources, respectively, in the presence of a photooxygenation catalyst.
Results: We successfully developed new photocatalysts for the oxygenation of aggregatedAβ, which can be activated under near-infrared (NIR) irradiation. Photooxygenation of
aggregated Aβ by the optimum catalyst (10 mol%) under light irradiation (λ = 780 nm) in
the presence of the cells attenuated the cytotoxicity of aggregated Aβ. The catalyst offered
oxygenation of Aβ in AD-model mouse brain lysate. Moreover, tissue permeability of NIR
light allowed for the catalytic photooxygenation of aggregated Aβ under the skin of amouse with NIR light irradiation.
1) Taniguchi, A.; Sasaki, D.; Shiohara, A.; Iwatsubo, T.; Tomita, T.; Sohma, Y.; Kanai, M.
Angew. Chem. Int. Ed. 2014, 53, 1382–1385.
2) Taniguchi, A.; Shimizu, Y. Oisaki, K.; Sohma, Y.; Kanai, M. Nat. Chem. 2016, 8, 974–
982.

26R-pm16

1. S. R. Chemler, M. T. Bovino. ACS Catal. 2013, 3, 1076.
2. M. Hatano, K. Moriyama, T. Maki, K. Ishihara. Angew. Chem. Int. Ed. 2010, 49, 3823; X.
Han, J. Kwiatkowski, F. Xue, K. W. Huang, Y. X. Lu. Angew. Chem. Int. Ed. 2009, 48, 7604.

Potent Mechanism-Based Sirtuin 2-Selective Inhibition by an in Situ Generated
Occupant of Selectivity Pocket, Substrate-Binding Site, and NAD+-Bindig Pocket.
○ Paolo MELLINI1, 伊藤 幸裕 1, 津元 裕樹 2, 李 頴 1, 鈴木 美紀 1, 徳田 奈津子 3,
柿澤 多恵子 4, 三浦 ゆり 2, 竹内 淳 3, Maija LAHTELA-KAKKONEN5, 鈴木 孝禎 1（1京府医大院医 , 2都健康長寿医セ研 , 3小野薬品工業 , 4早稲田大学理工 , 5イース
タンフィンランド大薬）
Among the known four HDAC classes, the third class called sirtuin family (SIRT1-7)
employ NAD+ as co-substrate to deacetylate histone and non-histone proteins. To date
several studies have established that sirtuins can regulate many biological processes suchas cellular metabolism, neuroprotection, apoptosis, inflammation, telomere maintenanceetc. [1] Growing reports evidenced that SIRT2 inhibition has beneficial effects onneurodegenerative diseases and depressive disorders. Furthermore, recent outputs suggestthat SIRT2 might play a key role in invasion and metastasis formation of malignancy byincreasing cell motility of cancer cells and its activity as tumour suppressor/oncogene
could be strictly connected with tumour grade. The perspectives on targeting SIRT2 as apotential anticancer drug target has made its way and nowadays development of morepotent and specific compounds is needed. [2, 3]. As potent SIRT2 inhibitors are urgently
needed starting from our previously reported 2-anilinobenzamide prototype as SIRT2
selective inhibitor, here we elucidated its binding mode on SIRT2 by X-ray crystal
structure. Next, targeting SIRT2 substrate binding site we not only strongly improved
SIRT2 inhibition by creating a set of SIRT2 inhibitors, but a novel potent
mechanism-based inhibitor named KPM-2 was discovered and validated. This latter was
found able to reduce the proliferation of MDA-MB231 and MCF-7 cancer cells showing
also a remarkable neurite outgrowth activity in N2a cells.

26U-am10S

Structure determination of bicyclic proline blocked α -amino acid peptide○ザイ ルーハン 1, 尾谷 優子 1, 竹内 恒 2, 嶋田 一夫 1, 大和田 智彦 1（1東大院薬 ,2
産業技術総合研究所）
Control of peptide conformations using conformational constraints has been one of thechallenging methods to reveal bioactive conformations of peptides and protein folding
process. We synthesized various hetero-dimers, in which polar or non-polar α-amino acidis coupled with the conformational constrained bicyclic amine (Figure 1). NMR studies
showed that all the dimers take a rigid cis-amide conformation. Next, we studied whether
the bicyclic structure will affect the conformation of neighboring α-amino acid. The
temperature dependence of the conformationally sensitive 3J(HαHN) coupling constants of
amide protons in various solvents and metadynamics calculations were applied. These
combined studies suggest that the overall structure of the dimer is converged to a limited
number of conformations. Hetero-trimers (αAA-αAA-bicycle) were also synthesized andwe found that the restriction inthebicyclic

skeletoncansuppress the rotation of themain chain on the N-terminal
up

to

two

α-aminoresidues (Figure 2).

[1] Haigis, M.C. et al. Annu Rev Pathol-Mech 2010, 5, 253–295. [2] Liu, P. Y. et al. Cell
Death Differ. 2013, 20, 503–514. [3] Jing, H. et al. Cancer Cell 2016, 29, 297–310. [4]Suzuki, T. et al. J. Med. Chem, 2012, 55, 5760-5773.

– 80 –acid26U-pm02

Direct α -Oxy C(sp3)-H Functionalization via Photoredox and Nickel Catalysis○孫 仲冬 1, 熊谷 直哉 1, 柴﨑 正勝 1（1微生物化学研究所）[Introduction] Transition-metal catalyzed cross-coupling reactions have become one of themost versatile carbon-carbon bond-forming reactions in organic synthesis. However, directC(sp3)-H cross-coupling still remains challenging in this well-developed research field.
With the surge of dual catalysis combining iridium photocatalyst with nickel catalyst,
unprecedented chemical transformations become possible.1-4 We herein report a direct
α-oxy C(sp3)-H arylation and acylation via visible light enabled photoredox and nickel
catalysis.
[Results] Nickel-catalyzed arylation and acylation reactions are facilitated by an
iridium-based photocatalyst and visible light to deliver α-functionalized ether products
from easily available starting materials. These reactions using exceptional conditions
exhibit good functional group tolerance and show broad substrate scope and applicability.

[References] (1) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433. (2)Zuo, Z.; Ahneman, D. T.; Chu, L. Terret, J. A.; Doyle, A. G.; MacMillan, D. W. C.
Science 2014, 345, 437. (3) Heitz, D. R.; Tellis, J. C.; Molander, G. A. J. Am. Chem. Soc.
2016, 138, 12715. (4) Shields, B. J.; Doyle, A. G. J. Am. Chem. Soc. 2016, 138, 12719.

26V-pm09

Catalytic Asymmetric Total Synthesis of Leptolyngbyolide C○崔 進 1, 渡辺 匠 1, 柴﨑 正勝 1（1微化研）[目的] Leptolyngbyolide C is a novel marine macrolide which exhibits remarkableantiproliferative activity against cancer cell lines. Fascinated by its complex structural
nature and intriguing biological properties, a study towards the total synthesis of thenatural product was initiated for the absolute configuration determination and improved
synthetic efficiency in the development of potential chemotherapeutic agents.
[結果] Efficient synthesis of the key fragments of leptolyngbyolide C were achieved in ahighly stereocontrolled manner using catalytic asymmetric direct thioamide-aldol reaction,a novel and practical methodology developed by our group, which are characterized by theuse of a soft Lewis acid/hard Brønsted base/hard Lewis base cooperative catalytic
system.1) The assembly of these fragments as well as the subsequent functional grouptransformations toward the total synthesis will be discussed.

Leptolyngbyolide C1) (a) Shibasaki, M. et al, J. Am. Chem. Soc., 2009, 131, 18244. (b) Shibasaki, M. et al, J.
Am. Chem. Soc., 2011, 133, 5554. (c) Shibasaki, M. et al, Tetrahedron, 2011, 67, 6539.

27I-pm02

Characterizing topology of surface ligands on liposomes○李 尚軒 1, 佐藤 悠介 1, 兵藤 守 1, 原島 秀吉 1（1北大院薬）【Purpose】The surface topology of ligands on liposomes is an important factor in active
targeting in drug delivery systems. Accurately evaluating the density of anchors andbioactive functional ligands on a liposomal surface is critical for ensuring the efficientdelivery of liposomes. For evaluating surface ligand density, it is necessary to clarify thaton the ligand-modified liposomal surfaces, some anchors are attached to ligands but someare not.
【Methods】To distinguish between these situations, a key parameter, surface anchor
density, was introduced to specify amount of total anchors on the liposomal surface.
Second, the parameter reaction yield was introduced to identify the amount ofligand-attached anchors among total anchors, since the conjugation efficiency is notalways the same nor 100%.
【 Results and Discussion 】 Combining these independent parameters, we derived:
incorporation ratio = surface anchor density × reaction yield [1]. The term incorporation
ratio defines the surface ligand density. Since the surface anchor density represents thedensity of polyethylene glycol (PEG) on the surfaces in most cases, it also determines
liposomal function. It is possible to accurately characterize various PEG and ligand
densities and to define the surface topologies. In conclusion, this quantitative methodology
can standardize the liposome preparation process and qualify the modified liposomal
surfaces.
[1] Lee S-H, Sato Y, Hyodo M, Harashima H: Topology of surface ligands on liposomes:
characterization based on the terms, incorporation ratio, surface anchor density, and reaction
yield. Biol. Pharm. Bull., 12, 1983-1994 (2016).

27Q-am03S

New acylated lignans from Mongolian Gobi plant Brachanthemum gobicum○ Batsukh ODONBAYAR1, 村田 敏拓 1, Javzan BATKHUU2, 佐々木 健郎 1（1東北医薬大 , 2モンゴル国立大）[Aims] The genus Brachanthemum (Asteraceae) is an endemic, ancient Asian flora that
contains ten species in the world, three of them distributes in Mongolian Gobi. The shrub
plant B. gobicum popularly known as an “Awful firewood”. In Mongolian traditional
medicine, water and ethanolic extracts of aerial parts are used against ectoparasites,
belonging to the Linognatus. In addition, the plant is widely used for livestock fodder inspring time. Herein, we are aimed to isolate and identify the effective compounds from B.
gobicum that may be related to the biological activities in traditional usage.
[Material and Methods] The aerial parts of B. gobicum (469 g) were extracted withacetone-H2O (4:1). The extract (63 g) was dissolved in H2O (1 L) and extracted with Et2O
(2 x 1 L) to obtain H2O (33 g), Et2O (17 g) and non soluble (13 g) fractions. Et2O fractions
were subjected to silica gel column and separated using HPLC columns to obtaincompounds. The structure of the isolated new compounds were elucidated byspectroscopic methods, including 1D, 2D NMR and mass experiments.
[Results and Discussion] Phytochemical investigation of aerial parts of B. gobicum
resulted in the ten new compounds including as phenolic compounds (1-3) and acylated
lignans (4-10). The new compounds were containing isovaleric acid in chemical structure,and it has been considered the responsibility for biological activity including as
anti-parasite and anti-plasmodial activities. Even if the results of the present study suggestthat chemical constituents of aerial parts including Et2O fractions were containing a newcompounds as an interesting structure, more though absolute stereochemistry, and their
responsibility for biological activity are need to evaluate.

27Q-pm06

An anti-mycobacterial sphingolipid and a new bromopyrrol alkaloid from anunidentified Indonesian marine sponge○ Delfly B. ABDJUL1,2, Hiroyuki YAMAZAKI1, Syu-ichi KANNO1, Ayako TOMIZAWA1,
Henki ROTINSULU2,3, Defny S. WEWENGKANG2, Deiske A. SUMILAT2, Kazuyo UKAI1,
Magie M. KAPOJOS3, Michio NAMIKOSHI1（1Tohoku Medical and Pharmaceutical
University, 2Sam Ratulangi University, 3University of Pembangunan Indonesia）
Marine sponges are a rich source for wide variety of metabolites with novel structuraland biological features. Therefore, we have investigated useful bioactive compounds fromtropical and sub-tropical marine sponges. In the course of our research program on
antibiotics against Mycobacterium smegmatis, we found that the EtOH extract of anunidentified Indonesian marine sponge inhibited the growth of M. smegmatis.
Bioassay-guided separation led to the isolation of a known dimeric sphingolipid derivative,
leucettamol A together with fourteen bromopyrrol alkaloids including a new congener. In
this presentation, the isolation, structure elucidation, and biological activities of thesecompounds will be presented.
The structure of 2 including the stereochemistry was revealed on the basis of thespectroscopic data and comparisons with those for the related compound.
Leucettamol A showed moderate inhibition zone of 12 mm against M. smegmatis at 50
μg/disc. This is the first study to show anti-mycobacterial activity of a bisfunctionalized
sphingolipid. Furthermore, bromoageliferin and 4,5-dibromopyrrol-2-methylcarboxylate
displayed weak PTP1B inhibitory activity among isolated compounds.

27Q-pm07S

Structures and biological activities of alkyl pyridinium alkaloids from anunidentified Indonesian marine sponge○ Wilmar MAARISIT1,2, Delfly B. ABDJUL1,2, Hiroyuki YAMAZAKI1, Hajime KATO1,
Henki ROTINSULU2,3, Defny S. WEWENGKANG2, Deiske A. SUMILAT2, Kazuyo UKAI1,
Magie M. KAPOJOS3, Michio NAMIKOSHI1（1Tohoku Medical and Pharmaceutical
University, 2Sam Ratulangi University, 3University of Pembangunan Indonesia）
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the greatest
infectious diseases worldwide as well as the human immunodeficiency virus (HIV) andmalaria. Approximately 9.6 million clinical cases, 1.5 million deaths from TB, and 0.4
million deaths from HIV-co-infected TB were estimated in 2014. Therefore, it is urgent
global demand to discover new anti-TB drugs with novel structural characteristics andmechanisms of action.
During our research on anti-mycobacterial substances from marine resources such asascidians, sponges, and microorganisms, our efforts revealed that the EtOH extract of anunidentified marine sponge, collected at Manado, Indonesia in 2013, exhibited an
inhibition zone against Mycobacterium smegmatis. Bioassay-guided isolation led to theidentification of two new cyclic 3-alkyl prydinium dimmers together with three known
analogues, cyclostellettamines A, C, and F. In this presentation, we describe the isolation,
structures, and biological activities of isolated compounds.
The structures of new compounds were assigned on the basis of their spectroscopic data
(1D and 2D NMR, FABMS, HRFABMS, UV, and IR.) and ESIMS/MS analyses. These
compounds showed antimicrobial activity against M. smegmatis with inhibition zones of
15–20 mm at 10 μg/disc.

– 81 –

27T-am07

Base-Induced Transformation of 2H-Azirines to Isoxazoles: Involvement of the
Deprotonation Pathway○寧 桜唐 1, 尾谷 優子 1, 大和田 智彦 1（1東大院薬）
Introduction 2H-azirine 1 can transform into oxazole 2 under photo irradiation, pyrolysis
and basic conditions. The mechanism of these reactions has been drawn a plenty ofinterests, and the reaction mechanism in basic conditions was proposed to be likely as
shown in eq 1 (Figure 1). We feel interested in this reaction because of similarity of
2H-azirines to nitrile compounds. We will study the possibility of involvement of
deprotonation process of 2H-azirines, yielding ketenimine intermediate 5 (Figure 1, eq 2),
which is a commonly observed in transformation of nitrile compounds. This is a newmechanism, not discussed in former studies.
Results and discussion The reaction of
base-induced isomerization reaction from
2H-azirine 1 to oxazole 2 was studied.
The present results have suggested thatboth the mechanism shown in eq 1 and eq
2 are reasonable. Calculation study has
revealed the participation of ketenimine
intermediate during the reaction, which is
generated by a ring-opening reaction on
α-deprotonated 2H-azirine anion 1-. Whenusing with less nucleophilic bases
including tert-BuOK and KH, thedeprotonation-triggered mechanism (eq 2)
Figure 1
became the major reaction pathway.

27T-pm05

Reversible Stereoselective Folding/Unfolding Fueled by the Interplay of
Photoisomerism and Hydrogen Bonding○ Chris OPIE1, 熊谷 直哉 1, 柴崎 正勝 1（1微生物化学研究所）
A linear molecular architecture equipped withcomplementary three-fold hydrogen bonding
units embedded with a photoswitchable
trans-tetrafluoroazobenzene
moietywassynthesized. Trans to cis photoisomerism of
the azobenzene unit induced drastic changes inentire molecular architecture due tointramolecular hydrogen bonding as evidenced
by NMR spectroscopy and size exclusion
chromatography. A minute stereogenic elementin the linear trans state enabled stereoselective
folding into the cis state, producing a globular
architecture with enhanced
chiroptical property.

27U-am05S

synthesis and evaluation of novel halogenated pseudocytidine derivatives forthe selective recognition of CG base pairs in triple-helix DNA○王 磊 1, 谷口 陽祐 1, 岡村 秀紀 1, 佐々木 茂貴 1（1九大院薬）[Objective] Triplex-forming oligonucleotides (TFO) that bind DNA in a sequencespecific manner might be used as selective repressors of gene expression and gene targeted
therapeutics. However, its formation is limited to homopurine-homopyrimidine sequences,
and a single base pair inversion interrupting a target homopurine region (e.g., AT or GC
inverted to TA or CG, respectively) can significantly destabilize triplex formation.
Previously, we have designed and synthesized novel pseudo-dC derivatives bearing
2-amino-3-methylpyridine unit for recognition of CG base pair with high selectivity andaffinity in anti-parallel triplex DNA1. In this study, we use halogen instead of methylgroup to evaluate its selectivity and affinity (Fig.1).
[Method and Result] At first, we synthesized the 3’ and 5’ hydroxyl protected novel
pseudo-dC derivatives bearing 2-amino-3-halogenpyridine unit. After that, new TFOs
containing novel pseudo-dC derivatives were synthesized by solid-phase synthesis method.
The triplex-forming ability of the synthesized TFO
was investigated by electrophoresis mobility shift
assays using FAM-labeled duplex DNAs. We foundthat TFOs incorporating haloAP-ΨdC showed
moderate affinity and selectivity towards the CGbase pair. Unfortunately, its effect was not better
than the TFOs incorporating MeAP-ΨdC. The lower
pKa of the haloAP-ΨdC diol compound comparedwith haloAP-ΨdC proved the much more difficult
protonation-forming of the N in the pyridine, which
contributes to triplex-forming significantly.
[1]H. Okamura, Y. Taniguchi, S. Sasaki, Angew. Chem. 2016, 128, 12633-12637.

– 82 –

25PA-am064S

25PA-am087

Expanding the amino acid repertoire of ribosomal polypeptide synthesis by
the artificial division of codon boxes○岩根 由彦 1, 人見 梓 2, 村上 裕 3, 加藤 敬行 1, 後藤 佑樹 1, 菅 裕明 1（1東大院理 ,2
東大院工 , 3名大院工）Design and Synthesis of Novel Anti-Alzheimer's Disease Agents Having
Furan-fused Perhydrophenantherene Skeleton○呉 詩慧 1, 杉本 健士 1, 松谷 裕二 1（1富山大院薬）[Introduction] We reported that serveral dihydrofuran-fused perhydrophenanthrenes(DFs) possessing a phenolic group showed the potent dendritic and axonal regeneration
activities in damaged neurons.1 Further structure-activity relationship studies suggested
that 8-ethoxy derivative or 8-phenylsulfanyl group with a 9-hydroxyl derivatives would be
more effective on the rat A-damaged neurons.2[Study] The recent studies on drug delivery through Blood-Brain Barrier indicated thatcationic compounds protonated on their amino group at a pH in vivo would be readilytransferred into a brain.3 Thus, we planned to install an amino group on DFs by a reductionof the cyano group. Additionally, we also examined a transition metal catalyzed amination
reaction with 8-iodo derivative 1

In ribosomal polypeptide synthesis, 61 sense codons redundantly code for 20
proteinogenic amino acids (pAAs). For example, the four codons in the valine codon box
code for valine by means of two specific tRNAs possessing GAC and cmo5UAC (cmo5U:
uridine 5-oxyacetic acid) anticodons (Fig. 1A). Here we have developed a method to
artificially divide such codon boxes and synthesize nonstandard polypeptides consisting ofmultiple nonproteinogenic amino acids (npAAs) along with the 20 pAAs1.
To achieve this goal, we reconstituted an in vitro translation system with 32 in vitrotranscribed tRNAs possessing SNN (S = G or C) anticodons (Fig. 1B). Among the 32
tRNA transcripts, 29 tRNAs were charged with 20 pAAs by endogenous aminoacyl-tRNA
synthetases, and the resultant 29 aminoacyl-tRNAs orthogonally decoded thecorresponding 28 NNS sense codons as well as the A
AUG initiation codon. The other three tRNAs were
Native tRNA
mixtureprecharged with three distinct npAAs by an artificial
In vitroaminoacylation ribozyme “flexizyme” and decoded thetranslation
corresponding GUC, CGC, and GGC codons to the
npAAs (Fig. 1B). By this strategy we have artificially B
29 tRNA
divided three codon boxes and expanded the aminotranscripts
3 precharged
acid repertoire up to 23. The concept was demonstrated vnpAA-tRNAs
by expressing a 32-mer linear peptide consisting of 20
In vitrotranslation
pAAs and 3 npAAs as well as a 14-mer macrocycliccontaining
three
distinct Fig. 1 (A) Native genetic code. (B) A
peptide“CM11-1”
reconstituted genetic code with three
N-methyl-amino acids along with D-tryptophan.
1st

U

C

2nd

A

G

Phe
Tyr CysSer
Stop Stop
Leu
Trp
His
Arg
C Leu Pro
Gln

U

A

G

1st

Asn SerThr
Lys Arg
Met
Asp
Val Ala
Gly
Glu
Ile

U

Phe
Leu
Leu
Leu
Ile
A
Met

C

2nd

A

G

Ser Tyr Cys
Ser
Trp
Pro His npAA
2
Pro Gln Arg
Thr Asn Ser
Thr Lys Arg
npAA
npAA
Ala Asp 3
1
G
Val Ala Glu Gly
U
C

3rd
U
C
A
G
U
C
A
G
U
C
A
G
U
C
A
G

Val

Val

GUU
GUC
GUA
GUG

Val

cmo5UAC

3rd
C
G
C
G
C
G
C
G

GAC

npAA1

GUU
GUC
GUA
Val GUG

npAA
1

GAC

(1) Matsuya, Y. et al. Bioorg. Med. Chem. Lett. 2012, 22, 449. (2) Matsuya, Y. et al.
Bioorg. Med. Chem. 2013, 21, 4459. (3) Kubo, Y. et al. Neurochem. Int. 2013, 62, 173.

Val

CAC

artificially divided codon boxes,
enabling polypeptide synthesis with 3

Reference 1. Y. Iwane et al. (2016) Nat. Chem. 8, 317. npAAs along with 20 pAAs.

25PA-am077

25PA-am126

Objective: We have found that ethyl 3-bromo-9-pyridinium-benz[f]indole-2-carboxylate(4) showed growth inhibitory activity on human glioblastoma cell1). For structure-activity
relationship, iodination of ethyl benz[f]indole-2-carboxylate (1) was carried out towards
the synthesis of pharmacologically active compounds.
Method: Iodination of (1) was examined for direct formation of pyridinium compound (3)under two types of conditions [morpholine-iodine complex (MI complex) and NCS/NaI].
Pyridine ring was incorporated to iodinated compound (2) with pyridine/I2 by stepwise
procedure.
Results and discussion: The reaction using MI complex gave only 3-iodo derivative (2) in
92%, while NCS/NaI gave the mixture of products (2) and (3). Although direct formationof 3-bromo-9-pyridinium compound (4) from (1) was found, 3-iodo-9-pyridinium
derivative (3) was obtained through 3-iodo derivative (2) by stepwise procedure. MI
complex could be a useful reagent for selective iodination of indoles.

Iminosugars, also known as iminocarbohydrates and azasugars, are importantcompounds as inhibitors of glycosidases, glycotransferases, and other enzymes.
Accordingly, iminosugars have often been used in the search for biofunctional compoundswith antiviral, antibacterial, anticancer, and/or antidiabetic activities. Especially,
C-glycosides of iminosugars are of interest because the C-linkage is more stable than the
O-linkage. In this poster, we report concise, efficient methods for stereoselective synthesisof iminosugars. We have recently reported methods for the synthesis of C-glycosides from
unprotected N-acyl-aldohexoses and unactivated ketones using amine-based catalysts via
aldol condensation-oxa-Michael additions.1 For the synthesis of iminosugars, we also used
unactivated ketones as nucleophiles. Our strategy for the synthesis of iminosugar
C-glycosides uses Mannich reactions of ketones with imines generated in situ fromcarbohydrate derivatives, which are followed by amino cyclizations via substitutions of thetosylated hydroxyl group. Various iminosugars were synthesized by our method. Our
method was useful for the gram scale synthesis of iminosugar C-glycosides as well as forthe small scale synthesis.

1)1.

Halogenation of Benz[f]indole Derivative towards the Synthesis of Antiglioma
Compounds○ Nyo Mi SWE1, 渡辺 敏子 1（1国際医福大薬）

Swe, et al. 135th Annual Meeting of PSJ (Kobe, 2015)

25PA-am084S

Synthesis of 2,3-Benzodiazepine Derivatives for Development of Novel
Neuroprotecting Agents○裴 東弘 1, 高山 亜紀 1, 松谷 裕二 1（1富山大院薬）【Introduction】2,3-Benzodiazepines are known as core structure of noncompetitive
2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptor
antagonists, such as CFM-2. In this study, our developed reaction, anion-accelerated
electrocyclization, was applied to synthesize unprecedented AMPA antagonists 3.1,2
Buchwald amination was planned to introduce amino group, an essential moiety to block
AMPA receptor.
【Result】Key intermediate 2 was synthesized from benzocyclobutene 1 and diazo ester
via sequential 4π-8π electrocyclic reaction. In this presentation, our attempt for analogue 3
would be discussed.
【References】
1. Matsuya, Y. et al., J. Am. Chem. Soc. 2006, 128, 13072.
2. Matsuya, Y. et al., Org. Lett. 2009, 11, 1361.

Synthesis of Iminosugar C-Glycosides via Mannich-Aminocyclization Reactions○ Lingaiah MARAM1, 田中 富士枝 1（1沖縄科学技術大学院大学）(a) S. Johnson, F. Tanaka, Org. Biomol. Chem., 2016, 14, 259-264.

25PA-pm045S

Effect of counter base of cytosine on deamination of 3-cyanovinyl-carbazole
mediated photo-cross-linked cytosine in DNA duplex○ Siddhant SETHI1, Minako OOE1, Sakamoto TAKASHI1, Shigetaka NAKAMURA1,
Kenzo FUJIMOTO1（1北陸先端科学技術大学院大学）[Purpose] In this study, to evaluate the role of hydrogen bonding in the deamination ofcytosine, 5 nucleobases (G, I, 5-nitroindole (N), 2-aminopurine (P) and nebularine (R)),
which show distinct pattern of hydrogen bonding with cytosine were adopted, and one ofthese nucleobases was incorporated at -1 position of CNVK on the CNVK-ODN.
[Method] The duplexes consisting of CNVK-ODNs and cODN(C) were irradiated (366
nm, 40 s) and incubated at 37ºC, and then irradiated (312 nm, 900 s) to split thecross-linked duplex. Resulting solutions were analyzed by ultra-high performance liquid
chromatography.
[Results] ODNs containing N, R, and P did not show any reactivity towards
deamination process, whereas, ODNs with G and I, respond to the deamination protocol
with ~5% and ~35% cytosine to uracil conversion observed respectively. Based onmolecular modeling simulations for the ODN duplex, it has been ascertained that P and R
do not engage in hydrogen bonding with cytosine, whereas, N forms a single hydrogenbond with cytosine. Whereas G forms three hydrogen bonds with cytosine, while in caseof inosine, there are two. The hydrogen bonding in exo-cyclic amino group of cytosine,
after photo-cross-linking is crucial for the process. Based on the deamination reaction
mechanism in cytosine deaminase, the leaving ammonia is usually hydrogen bonded to the
enzyme active site. In this case as well incoming nucleophile attack is favored when thetarget amino group is engaged in H-bonding in the cross-linked duplex, where, theexo-cyclic amino group forms hydrogen bond with adjacent base due to perturbation in theplanar structure of cytosine, while it obstructs the attack when unbound.
[Conclusion] Thus, an optimum hydrogen-bonding pattern is required to carry out thephoto-cross-link induced cytosine deamination.

– 83 –

25PA-pm097S

Polyalongirin A , a novel skeleton compound from Polyalthia longifolia○郭 佳宜 1, 張 誌益 1, 林 昀生 2（1台灣屏東科技大學 , 2台灣美和科技大學）
A novel skeleton, Polyalongirin A (1), was isolated from the leaves and barks of
Polyalthia longifolia. Polyalongirin A (1), contain an aprophine alkaloid and a halimane
diterpene linkage skeleton, it also be the first natural N-1 and C-20 linked compound. The
structure of the new secondary metabolite, including their configurations, was establishedon the basis of an extensive spectroscopic analysis, including 1D and 2D NMR (1H-1H
COSY, HMQC, HMBC, and NOESY), and by comparison of their NMR data with thoseof the related compounds. The relative stereo structure of Polyalongirin A (1) was also
confirmed by a single-crystal X-ray diffraction analysis.

Polyalongirin A

X-ray structure of Polyalongirin A

25PB-am035

Simulation time necessary for diminishing the dependency of protein
structures on the crystal condition○斉 非 1, 米田 友貴 1, 根矢 三郎 1, 星野 忠次 1（1千葉大院薬）[Objective] In our previous studies, we suggested that multiple crystal structures of asingle kind of protein could be classified into several groups from the viewpoint ofstructural similarity. A major factor causing these structural separations is the space groupof crystals, in which crystallizing agents have an influence on the packing of proteins in
crystal. It is expected that the separated cluster groups can be merged into one group if
molecular dynamics (MD) simulations are performed for the proteins without crystallizing
agent. It is interesting to know how long it takes for cluster groups to be merged. In orderto answer this question, we carried out MD simulations on the crystal structures of hen
egg-white lysozyme (HEWL), sperm whale myoglobin (Mb), human serum albumin(HSA), hemoglobin (Hb).
[Result] As for HEWL, 336 crystal structures are classified into 5 groups. From eachgroup, 5 representative crystal structures were selected in terms of the absences of amino
mutation and missing residues. 25 HEWL models built from 25 crystal structures were
calculated by MD simulation. As the result,the difference among the initial crystal
structures disappeared and all the clustergroups were merged into one group at 20 ns.
In case of Mb, 20 crystal structures wereselected from 4 groups. All the clustergroups were merged into one group at 25 ns.
As for HSA and Hb, it takes more than 80 ns
to merge all the cluster groups into one group
because of their large-mass weight.

25PB-am189

Active bufadienolide compounds induce G2/M phase arrest in humanglioblastoma cell line U-87
○韓 玲玉 2,1, 袁 博 1, 林 秀樹 1, 辺 宝林 2, 高木 教夫 1（1東京薬大薬 応用生化 ,2
中国中医科学院 中薬研究所）【Aims】We have demonstrated the growth inhibitory effects of bufadienolides in ahuman glioblastoma cell line U-87. We further demonstrated that gamabufotalin, an active
bufadienolide compound, downregulated the percentages of regulatory T cells, suggesting
its capability to enhance antitumor immunity. In this study, the effects of arenobufagin(Areno) and hellebrigenin (Helleb), two major active bufadienolides, were investigated in
U-87 cells by focusing on growth inhibition, cell membrane damage, cell cycle arrest, andDNA fragmentation. 【Methods】Cell viability, cell cycle arrest, and DNA fragmentation
were evaluated by XTT assay, flow cytometric analysis, and DNA gel electrophoresis,
respectively. Cell damage assay was measured using the lactate dehydrogenase(LDH)-cytotoxic test kit. Furthermore, the expression of cell cycle regulatory proteins wasanalyzed by Western blot assay. 【Results and Discussion】A significant decrease in cell
viability was observed in a dose-dependent manner in U-87 cells after treatment with
Areno and Helleb. Up to 40 ng/ml of the two bufadienolides induced little LDH leakage inthe cells, suggesting the unlikely involvement of a necrosis-like phenotype in thecytotoxicity. The DNA electrophoresis also showed no DNA fragmentation in
Areno-treated cells, indicating no contribution of apoptosis induction. On the other hand, aremarkable increase in the number of cells in G2/M phase was observed in U-87 cells in adose- and time-dependent manner when treated with Areno and Helleb, concomitant witha decrease in the number of cells in both G0/G1 and S phase. Furthermore, a significant
downregulation of the expression level of Cyclin B1, a key molecule for G2/M transition
during the cell cycle, was observed. These results suggest that the cytotoxicity of Areno
and Helleb was attributed to G2/M arrest associated with the downregulation of Cyclin B1.
Further investigation of the detailed mechanism underlying their cytotoxicity is ongoing.

25PB-am194S

The Downregulation of the Energy Metabolism by Brain Metastatic Melanoma
Cell Derived Exosomes in Human Brain Capillary Endothelial Cell Line;hCMEC/D3○陳 瓊芳 1,2, 内田 康雄 2, 黒田 広樹 2, 梅津 美奈 2, 八木 悠太 2, 立川 正憲 2,
寺崎 哲也 2（1ハイデルベルグ大医 , 2東北大院薬）[Purpose] Brain metastatic cancer cell derived exosomes have been shown to trigger the
break-down of the BBB by interfering with the assembling of actin resulting in disrupted
tight junctions [Nat Commun. 6:6716 2015]. However, this study is limited to the effectsof miRNA181c contained in exosomes. The purpose of the present study is to identify
which cellular events in the BBB’s endothelial cells are mainly affected by brain
metastatic melanoma cell derived exosomes. [Method] Exosomes were extracted from thebrain metastatic melanoma cell line SK-Mel 28 and the human brain endothelial cell line
hCMEC/D3 was used as in vitro BBB model. To screen which molecules are affected byexosomes, exosome-treated hCMEC/D3 cells were compared with a non-treated control
by using the comprehensive proteomics method SWATH. [Results and Discussion] About
1,200 proteins were reliably detected in SWATH analysis. As it is well known, miRNAgenerally inhibits mRNA translation and thereby downregulates protein levels. Therefore,
our focus was primarily on significantly downregulated proteins; downregulation of ≤0.7
(exosome treated/untreated) with a B&H adjusted p-value of ≤0.05 and no significant
upregulation in any other peptides of the same protein. Based on these criteria, 137 out of
about 1200 proteins were selected as potential candidates. The DAVID enrichment
analysis of these 137 proteins allowed us to identify energy metabolism pathways, i.a. theoxidative phosphorylation (7 proteins), citrate cycle (4 proteins), pyruvate metabolism (3proteins), fatty acid metabolism (3 proteins) and Val, Leu, Ile degradation (4 proteins) as
most reliably downregulated pathways by exosome treatment. We therefore conclude thatbrain metastatic melanoma cell derived exosomes could impair the energy metabolism of
the BBB’s endothelial cells. This could be one of the essential cellular events to disrupt thetight junctions in the BBB and facilitate brain metastasis of melanoma cells.

25PB-am100

25PB-pm085

Methamphetamine (METH) is an addictive psychostimulant that induces neurotoxicity.
Our preliminary results showed that complement factor H (CFH) in the hippocampus andventral tegmental area (VTA) was significantly increased in the METH-induced
conditioned place preference (CPP) rats. CFH is an essential regulatory protein that plays
an inhibitory role in the activation of the complement system. However, the distribution of
CFH in above-mentioned brain regions is unclear. In this study, we used
immunofluorescence staining to detect the expression of CFH in the hippocampus and
VTA of METH-induced CPP rats. We observed strong signals of CFH in the cell bodies of
CA1 pyramidal neurons. CFH was also highly localized in dopaminergic neurons of VTA
as indicated by double immunofluorescence staining for TH and CFH. As some recent
studies indicate that the complement system is involved not only in clearing out damaged
cells also in brain development and synapse pruning. So we hypothesized that CFH in the
hippocampus may be associated with memory formation in METH addition by engaging
in pyramidal neurons’ modification. CFH in the VTA may play a protective role inoveractive dopaminergic neurons. In addition, MALDI-MSI was used to detect the
distribution of molecules with molecular weights less than 1000 in the brain slices of
METH-induced CPP rats. The distribution of and some unidentified lipid in CPP rats
brain differs from that in normal rats.

Eudebeiolide B is a eudesmane-type sesquiterpenoid compound isolated from Salvia
plebeia R. Br which is no known about biological activity. In this study, we investigatedthe effects of eudebeiolide B on receptor activator NF-kB ligand (RANKL)-induced
osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. In mouse bonemarrow macrophage (BMMs), eudebeiolide B suppressed RANKL-induced osteoclastdifferentiation in BMMs and bone resorption. Eubeiolide B suppressed expression of
NFATc1 and c-fos, as transcription factor induced by RANKL also, it attenuatedRANKL-induced osteoclastogenesis related genes expression such as Cathepsin K, MMP9and DC-STAMP. In molecular mechanism, eudebeiolide B inhibited phosphorylation of
CREB, Btk and phospholipase Cγ2 (PLCγ2) in RANKL-induced calcium signaling. In
ovariectomized (OVX) mouse model, oral administration of eudebeiolide B prevented
OVX-induced bone loss based on bone mineral density and contents, micro-architecture
parameters and serum level of bone turnover maker. These data suggest that eudebeiolide
B inhibited RANKL-induced osteoclastogenesis through calcium signaling and prevents
OVX-induced bone loss. Therefore, eudebeiolide B may be promising as new therapeutic
agent for osteoclast-related disease including osteoporosis, rheumatoid arthritis andperiodontitis.
Fig. Micro–CT images of the proximal femurs fromsham-operated group, OVX, OVX + Eudebeiolide B andOVX + Alendronate mice were obtained

CFH in hippocampus and VTA of CPP rats may be associated with METH
addiction○许 嘉旻 1, 赵 欣 1, 孙 懿 1, 蒲 小平 1（1北京大学 药学院）Eudebeiolide B inhibits osteoclasto genesis and prevents ovariectomy-inducedbone loss by regulating RANKL-induced calcium signaling○李 承在 1（1韓國生命工学研究院）– 84 –

25PB-pm086

Study of the UV Light Conversion of Feruloyl Amides from Portulaca
oleracea and Their Inhibitory Effect on IL-6-Induced STAT3 Activation○李 勝雄 1（1韓国生命工学研究院）
Two new feruloyl amides, N-cis-hibiscusamide (5) and (7′S)-N-cis-feruloylnormetanephrine(9), and eight known feruloyl amides were isolated from Portulaca oleracea L. and thegeometric conversion of the ten isolated feruloyl amides by UV light was verified. The
structures of the feruloyl amides were determined based on spectroscopic data andcomparison with literature data. The NMR data revealed that the structures of the isolated
compounds showed cis/trans-isomerization under normal laboratory light conditions.
Therefore, cis and trans-isomers of feruloyl amides were evaluated for their convertibility
and stability by UV light of a wavelength of 254 nm. After 96 h of UV light exposure,23.2%–35.0% of the cis and trans-isomers were converted to trans-isomers. Long-term
stability tests did not show any significant changes. Among all compounds and conversion
mixtures collected, compound 6 exhibited the strongest inhibition of IL-6-induced STAT3
activation in Hep3B cells, with an IC50 value of 0.2 μM. This study is the first verificationof the conversion rates and an equilibrium ratio of feruloyl amides. These results indicatethat this natural material might provide useful information for the treatment of various
diseases involving IL-6 and STAT3.

Fig. Inhibitory effect on IL-6-induced
STAT3 activation

25PB-pm089

Evaluation for antitumor response and immune activity of Phytochemicals
from Zingiber officinale Roscoe
Minji SOHN1, Jehyung LEE1, ○ Yongkyu LEE1（1Bio-Science & Engineering,Dongseo University）
Zingiber officinale Roscoe has been widely used as a folk medicine to treat various diseases,
including cancer. This study aims to re-examine the therapeutic potential of co-administrationof natural products and cancer chemotherapeutics. Candidate material for this project, αzingiberene, was extracted from Zingiber officinale Roscoe, and α-zingiberene makes up 35.02± 0.30% of its total essential oil. α-Zingiberene showed lower IC 50 values than 150 μg/mL
in SNU-1, HePG2 cells,
and showed lower IC 50 values than 65 μg/mL in U937, L1210 cells. These values are a little bit higher than IC 50 values of general essential oil in thosecells.
Our study found that α-zingiberene inhibited the increase of white blood cell number, which
was normally increased by the injection of lymphoblast cells, P388D1, and α-zingiberene
increased lymphocyte percentage compared to the control. Tumor inhibition rate in αzingiberene-treated or glivec treated group was 7.79%, 15.01% each. Apoptosis indexes of thecontrol, α-zingiberene and Glivec groups were 4.22±1.02, 5.02±1.46 and 9.01±2.01,
respectively, in which only the Glivec-treated group showed a significance. α-zingiberenetreated group increased T-lymphocyte and B-lymphocyte proliferation activities compared tothe control group, which was more significant in T-lymphocyte than in B-lymphocyte
proliferation activity. These findings suggest that α-zingiberene does not have achemotherapeutic effect on tumor incidence, but it has a repressive effect on P388D1
lymphocyte implantation. Furthermore, this protective effect of α-zingiberene from P388D1
lymphocyte implantation is considered the result from the increased activity of tumor
immunogenicity through increased T-lymphokine production and increased percentage oflymphocytes. α-zingiberene is considered to be worth furthermore study to clarify the immune
mechanism from IL-2 production.

25PB-pm087

25PB-pm090

Salvia plebeia R.Br. (SPRB) is a natural resource that exhibits various biologicalactivities. However, its effects on inflammatory diseases are not yet well characterized.
This study aimed to evaluate the inhibitory effects of a compound derived from SPRB oninterleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) activation.
The chemical structure of active compounds isolated from the EtOAc-soluble fraction of
SPRB were elucidated by comparison with spectroscopic nuclear magnetic resonance(NMR) and electrospray ionization mass spectrometry (ESI–MS) data in the literature,
which resulted in the identification of 22 known compounds. All of the isolated
compounds were evaluated for potentially higher inhibitory effects on IL-6-induced
STAT3 activation in Hep3B cells using a luciferase reporter assay. Furthermore, theprotein levels of p-STAT3, p-ERK, and p-JAK2 in IL-6 induced U266 cells were regulated
in the presence of cirsimaritin from SPRB by western blot assay. Based on these findings,
we suggest that SPRB has the potential to inhibit IL-6-induced STAT3 activation andshould be considered in functional food and pharmaceutical applications.

Curcuma longa is a perennial plant that is widely used in cooking and in folk medicine.
Here, we evaluated the effects of extracts of the aerial parts of C. longa on inflammatory
processes in RAW264.7 macrophage cells. Dried aerial parts of C. longa were extractedwith methanol and partitioned successively with CH2Cl2 and n-BuOH. This n-BuOH
fraction (0–40 μg/ml) significantly suppressed the lipopolysaccharide-mediated inductionof nitric oxide, prostaglandin E2, and pro-inflammatory cytokines. Western blotting foundthat the levels of nitric oxide synthase and cyclooxygenase-2 were also reduced in aconcentration-dependent manner, in the absence of cytotoxicity. The major components
present in this extract were isolated and chemically characterized using ultra-performanceliquid chromatography-quadrupole time-of-flight mass spectrometry and nuclear magnetic
resonance
spectroscopy.
Fourflavonoids
were
identified:
Quercetin
3-(2Gal-rhamnosyl-robinobioside) (1); Quercetin 3-rutinoside (2); Quercetin
3-rhamnosyl-(1→2)-rhamnoside (3); and Quercetin-3-O-rhamnoside (4).

Inhibitory effects of IL-6-induced STAT3 activation of bio-activecompounds
derived from Salvia plebeia R.Br○魯 文喆 1（1韓国生命工学研究院）

Chemical constituents and anti-inflammatory activity of the aerial parts of
Curcuma longa○李 雨松 1（1韓国生命工学研究院）

Fig. Chemical structures of secondary metabolites 1–4 isolated from the butanol
fraction of the aerial parts of C. longa.

Fig. Inhibitory effect of cirsimaritin from Salvia plebeian R. Br. on IL-6 signal pathway

25PB-pm088

Eudesmane-type sesquiterpenoids from Salvia plebeia inhibit IL-6-induced
STAT3 activation○張 賢在 1（1韓国生命工学研究院）
Seven eudesmane-type sesquiterpenoid lactones and the known plebeiolide C wereisolated from an ethanol-soluble extract of the aerial parts of Salvia plebeia R. Br. Theirstructures were determined via NMR and MS, and their absolute configurations were
elucidated using ECD, and X-ray crystallographic analysis, as well as the modified
Mosher ester method. All isolates were evaluated for their inhibitory effects on
IL6-induced STAT3 promoter activation in stably transfected Hep3B cells. Of these
isolates, eudebeiolide D exhibited an inhibitory effect with the IC50 value of 1.1 μM.

26PA-am032

Chemical Studies on the Ghanaian Plant Thonningia sanguinea Vahl (Part 1)
Ama K. THOMFORD1,2, Reda F. A. ABDELHAMEED1,3, ○山田 耕史 1（1長崎大院医歯薬 , 2Department of Biomedical and Forensic Sciences, University of Cape
Coast, 3Faculty of Pharmacy, Suez Canal University）
Research on the traditional use of medicinal plants continues to play a criticalrole in expanding the scope of natural product chemistry. The Ghanaian parasitic plant
Thonningia sanguinea is used in traditional medicine for the management of pain andinflammatory diseases such as arthritis and bronchial asthma. There are a few
pharmacological studies on its crude extracts however, there is scanty data on its chemical
profile. This study therefore aimed to isolate and characterize the bioactive compounds
from this plant.
We report on the isolation of two cerebroside molecular species TSC-1 (41mg) and TSC-2 (92 mg) from the n-hexane fraction of T. sanguinea (3.5 kg, dried weight).
The structure of these cerebrosides using spectral analyses (FAB-MS, 1H-NMR and
13
C-NMR) revealed a normal phytosphingosine-type cerebroside possessing a 2-hydroxy
fatty acid and β-glucopyranose moieties. These glucocerebrosoides are well known for
their wide range of bioactivities including anti-inflammation and analgesia which may be
responsible for the traditional use of this plant.

Fig. New eudesmanolides (1–7) were isolated from Salvia plebeia R.Br., and the structures
were elucidated. The absolute configurations of compounds (1–8) were determined using
ECD, X-ray crystallography, and the modified Mosher’s ester method. Of all the isolates,
new sesquiterpenoid (4) showed the most significant IL-6/STAT3 inhibitory effect.

– 85 –

26PA-am085

Jiao-Tai-Pill and Cinnamaldehyde Alleviates Metabolic Disorder in SHR/
NDmcr-cp Rats
○高 明 1, 張 露 2,1, 根岸 裕子 1, 劉 銅華 2, 孫 文 2, 池田 克巳 1（1武庫川女大薬 , 2北京中医薬大）
1. Jiaotiao Pill (JTP), composed of Coptis chinensis and cinnamon, is one of the mostwell-known traditional Chinese medicines from Han’s Books on Medicine in 1522. It used
to coordinate yin and yang. Resent studies had reported that JTP have therapeutic effects
on diabetes. It can reduce the fasting blood glucose and food and water consumption.
Cinnamaldehyde (CA), one of the major active constituent isolated from cinnamon, has abiological activity on anti-hypertension and anti-hyperlipidemia. Here we investigated theeffects of JTP and CA by SHR.Cg-Leprcp/NDmcr (SHR/cp) rats, a obese model of
spontaneously hypertension, on the coexistence heterogeneous of metabolic syndrome.
2. 7-week-old Male SHR/cp rats were chosen according to the level of body weight, total
triglyceride and systolic blood pressure (SBP). They were randomly divided into control,
JTP (0.6g/kg) and CA (40mg/kg) groups. Age-matched male WKY rats were used as
normal controls. All rats fed with a high-fat and high-cholesterol special diet throughout
the experiment. Body weight and food intake were recorded every week. Blood pressure
was determined by the indirect tail-cuff method every two weeks. After 6 weeks treatment,
all the rats have sacrificed and organs weight have measured.
3. Results have showed that obese SHR/cp rats exhibited higher SBP compared to normal
control group rats. After 4 weeks of JTP treatment, decreased SBP were observed. The
same as CA group. Furthermore, body weight of rats in JTP group is less than other
SHR/cp rats from 2 weeks of administration. So as the daily food consumption.
Meanwhile rats in CA group body weight no less than that of control group.
4. These observations suggested that JTP may be have an alternative treatment for
metabolic syndrome by reducing blood pressure and body weight better than use CA
alone.

26PA-am116

Screening study on TRAIL-resistance overcoming activity from Celtis
tetrandra and Amonum villosum
Prapairat SEEPHONKAI1,2, 荒井 緑 1, 石川 直樹 1, 小谷野 喬 3,
Thaworn KOWITHAYAKORN4, ○石橋 正己 1（1千葉大院薬 , 2マハサラカン大
学理 , 3テムコ , 4コンケン大農）[Objective]
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is recently
considered promising cancer chemotherapeutic approach due to its potent and selective
apoptosis inducement in variety of tumor cells with non-cytotoxicity against normal cells.
Therefore, searching for new bioactive natural products on TRAIL-resistance overcoming
activity using human gastric adenocarcinoma (AGS) cell lines is the aim of this research.
[Methods and Results]
Numbers of the Thai plant extracts have been tested by comparing the cell viability of
TRAIL-resistance AGS cell lines with the presence and absence of TRAIL. Based on the
results of TRAIL-resistance overcoming activities the Celtis tetrandra (bark) and Amonum
villosum (rhizome) were chosen as hit samples and their active constituents have beenchemically investigated. The differences in cell viability of screening extracts of C.
tetrandra (bark) and A. villosum (rhizome) were 30% at 10 μg/mL and 60% at 10 μg/mL,
respectively. Bioassay-guided fractionation of the active ethyl acetate extracts led to theisolation of compounds in classes of flavanols such as (-)-catechin, (+)-afzelechin, andflavonessuchas(-)-epiafzelechin
from
the
C.
tetrandra and5-hydroxy-3,7,4’-trimethoxyflavone and 3,5,7,4’-tetramethoxyflavone from the A.
villosum. The chemical structures and the activity of the isolated compounds are reported
herein.

26PA-am123S

Characterization of proanthocyanidin oligomers of Ephedra sinica○ Joanna Justimbaste OREJOLA1, Yosuke MATSUO1, Yoshinori SAITO1,
Takashi TANAKA1（1Grad. Sch. Biomed. Sci., Nagasaki Univ.）[Objective] Activities of Ephedra sinica were mainly attributed to ephedrine, and lessemphasis was given on quantitatively major constituents, proanthocyanidin oligomers.
This study aimed to characterize the proanthocyanidin oligomers by chemical degradation.
[Methods] Proanthocyanidin oligomers were obtained by successive column
chromatography using Sephadex LH-20 and Diaion HP20. The structure of the oligomers
were characterized by 13C NMR spectroscopy and by acid-catalyzed phloroglucinolysis
and thiolysis with mercaptoethanol.
[Results & Discussion] The 13C NMR spectrum and HPLC analysis of the thiol
degradation products indicated that the oligomers are proanthocyanidins mainly composedof epigallocatechin unit. This was also supported by phloroglucinolysis that affordedmonomeric products 1 as the major products. Presence of epicatechin and gallocatechinunits were also shown by production of 2 and 3 as minor products. HPLC analysis of the
products suggested high degree of oligomerization because the peaks attributable toterminal units were very small comparedto those of extension units. In the13
C-NMR
spectrum,thesignals
attributable to C-ring C-2 methine wererelatively small compared to the C-3
methine signals, suggesting occurrence ofA-type linkages. This was also supported
by appearance of signals at δ 153
assignable to D-ring C-7 of A-type
proanthocyanidins. Further studies on
degradation products are in progress.

26PA-pm020

The peel constituents and anti-inflammatory activities of Citrus grandis
Ping-Chung KUO1, Hsin-Yi HUNG1, Chia-Wei CHUANG1, Tsong-Long HWANG2,
Young-Ji SHIAO3, ○ Tian-Shung WU1（1School of Pharmacy, National Cheng
Kung University Hospital, College of Medicine, National Cheng Kung University,
2
School of Traditional Chinese Medicine, Chang Gung University, 3National
Research Institute of Chinese Medicine, Ministry of Health and Welfare）
A series of chromatographic separations of the peel ethanolic extract of Citrus grandis has
led to the isolation of forty compounds, including seventeen coumarins, eight flavonoids,
two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five othercompounds, respectively. The chemical structures of the forty compounds were elucidated
on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and Mass
analysis. Among the isolates, isomeranzin, 17,18-dihydroxybergamottin, epoxybergamottin, rhoifolin, vitexicarpin and 4-hydroxybenzaldehyde displayed the most significant
inhibition of superoxide anion generation and elastase release with IC50 values ranged
from 0.51 to 7.57 μM and 0.43 to 4.33 μM, respectively.

26PA-pm021

Anti-Inflammatory Constituents Isolated from Solid-State Fermented Antrodia
cinnamomea Mycelium
I-Chuan YEN1, Shih-Yu LEE2, ○ Li-Shian SHI3（1Graduate Institute of Medical
Science, National Defense Medical Center, 2Graduate Institute of Aerospaceand Undersea Medicine, National Defense Medical Center, 3Department of
Biotechnology, National Formosa University）
Antrodia cinnamomea, belonging to the Antrodia genus, is a medicinal fungus in Taiwan.
The mycelium of this fungus were prepared by solid-state or liquid fermamtation andbecome as a health food in Taiwan for the past few years. In this study, we separated four
newcompounds,
4,5,7-trimethoxy-1,3-benzodioxole(6),1,2-dihydroxy-3,6dimethoxy-4-methylbenzene (8), antrolone (10), and antrocene (11), together with nine
known compounds from the ethanol extracts of solid-state fermented A. cinnamomea
mycelium. Therein, compounds 3, 5, 10, and 12 were able to reduce the nitric oxide (NO)levels in LPS-stimulated RAW 264.7 cells. The IC50 of compounds 3, 5, 10, and 12 were5.75 ± 0.89, 7.85 ± 0.49, 16.98 ± 0.10, and 0.31± 0.15 μM, respectively. The results
suggest that compounds 3, 5, 10, and 12 contribute to the anti-inflammatory effects of theethanol extract of solid-state fermented A. cinnamomea mycelium. Our findings suggested
that these four compounds can be used as candidate for anti-inflammatory drugs.

26PA-pm022

Components isolated from Cinnamomum kanehirae with growth promotion
effects on Antrodia cinnamomea○ Lih-Geeng CHEN1, I-Hung SHEN1（1Department of Microbiology, Immunology
and Biopharmaceuticals, National Chiayi University）【 Aim 】 Cinnamomum kanehirae (Lauraceae) is an endemic tree in Taiwan which
distributed in broadleaf forest of 450-2000 m mountains. The woods of C. kanehirae has
been used for cultivate the Antrodia cinnamomea in Taiwan. In present, the constituents of C.
kanehirae wood and its growth promotion effects on A. cinnamomea were reported.
【Methods】C. kanehirae wood was extracted with methanol. The methanolic extract wassuspended in water and then partitioned with ethyl acetate to obtained ethyl acetate layer,
precipitate, and aqueous layer. The ethyl acetate layer and precipitate were purified by
Sephadex LH-20 column, silica gel column, and LiChrospher RP-18 column. Steam
distillation method was used to prepare the essential oil of A. cinnamomea wood. Fourstrains of A. cinnamomea, BCRC37848, BCRC37849, BCRC37850 and Chu1030615, wereused to evaluate the mycelium growth promotion effects of compounds.
【Results & Discussion】Six compounds, sesamin, 4-hydroxysesamin, quercetin, taxifolin,(R)-(+)-5-(2,3-dihydroxypropyl)-1,3-benzodioxole, and cis-1,4-dihydroxy-1-isopropyl4-methylcyclohexane, were isolated from the C. kanehirae wood. 4-Hydroxysesamin (10μg/ml)-added malt extract agar plate showed significant growth promotion in four strains of
A. cinnamomea. Essential oil of C. kanehirae at 0.01% in malt extract agar has the best
growth promotion. However, cis-1,4-hydroxy-1-isopropyl-4-methylcyclohexane-added
malt extract agar plate showed inhibitory effect on growth. The results can be used toenhance the growth rate of cultivated A. cinnamomea.

– 86 –

26PA-pm023

Hypoglycemic Constituents from the Pericarps of Trapa natants L.
○ Hui-Chi HUANG1, Chien-Liang CHAO2, Chih-Hua CHAO3,4, Yueh-Hsiung KUO1
（1Department of Chinese Pharmaceutical Sciences and Chinese Medicine
Resources, China Medical University, 2Herbal Medicine R & D Department, Sinphar
Pharmaceutical Co., Ltd., 3School of Pharmacy, China Medical University, 4Chinese
Medicine Research and Development Center, China Medical University Hospital）
Trapa natans L., commonly known as the water chestnut or water caltrop, is an aquatic
floating plant native to Eurasia, Africa and Asia and is grown as a food product ormedicinal plant in Taiwan, China and parts of Southeast Asia. In this study, two newtannins (1-2), one new neolignan (14), one new norlignan (17), and twenty known
compounds were isolated from the pericarps of T. natans. The structures of 1, 2, 14, and17 were elucidated by spectroscopic and spectrometric methods, including 1D and 2D
NMR experiments. Compounds 1–13, 16–18, 20, 21, and 24 were screened for glucose
uptake in mouse skeletal muscle cells (C2C12 myotubes). A series of hydrolysable tannins(1–8), lignan (13), flavonoid (16), norlignan (17), and phenolic compounds (18, 20, 21,
and 24) displayed the enhancing activity on glucose uptake in C2C12 myotubes.

26PA-pm026

The Constituents from the Stems of Cissus assamica○ Yu-Yi CHAN1, Chiu-Yuan WANG1, Tian-Shung WU2（1Department of
Biotechnology, Southern Taiwan University of Science and Technology, 2Schoolof Pharmacy, National Cheng Kung University）
Fifty-five compounds were isolated from the fresh stems of Cissus assamica, including
fourteen benzenoids, eleven triterpenes, nine steroids, five tocopherols, five chorophylls,
four flavonoids, two benzoquinones, two tannins and three other compounds. Theirstructures were determined by 1D and 2D NMR and mass spectral data, and wereidentified by comparison of their spectral data with those reported in the literature. Amongthese isolates，1, 2-bis-(5-γ- tocopheryl)ethane was reported for the first time from thenatural sources. The bioactivity evaluation of the isolated compounds is in progress.

26PA-pm024

26PA-pm027【Aim】 Acne is a common skin condition with sebum overproduction, hyperkeratosis,
bacterial growth, and inflammation. Therefore, we explored the anti-acne effects ofpomegranate and expect the extracts can be used in clinic.
【Method】 In vitro and in vivo anti-acne effects included anti-bacteria, anti-lipase,anti-proliferation, anti-inflammation and anti-ear edema were performed using 70%
acetone pomegranate extract (PG-E) and four hydrolysable tannins.
【Result】 In this study, we found that PG-E significantly reduced P. acnes-induced
edema in Wistar rat ears. Therefore, an evaluation platform using multiple pathogenic
mechanisms of acne was established to explore the anti-acne effects of pomegranate.
Results showed that PG-E inhibited bacterial growth and lipase activity. Through a
bioguided-fractionation-isolation system, four hydrolysable tannins, punicalagin (1),punicalin (2), strictinin A (3), and granatin B (4), were isolated. Compounds 1 and 2 hadgreater anti-bacterial activities and anti-testosterone-induced HaCaT proliferative effects
than the others. Compounds 1, 3, and 4 displayed lipase inhibitory effects. Compound 4
decreased cyclooxygenase-2 expression and downregulated prostaglandin E2 production inheat-killed P. acnes-treated RAW 246.7 cells. In conclusion, PG-E is abundant inhydrolysable tannins which display multiple anti-acne capacities, including anti-bacterial,anti-lipase, anti-keratinocyte proliferation and anti-inflammatory actions. Hence, PG-E has
great potential in application of anti-acne and skin-care products and punicalagin (1), themost effective component in PG-E, can be employed as a quality control marker.

Aldol condensation and subsequent reduction were applied to prepare twenty-one
dihydrochalcone and 1,3-diphenylpropane derivatives. The synthetic products were
subjected to evaluate NO inhibition in LPS-activated mouse peritoneal macrophages.
Among
the
testedcompounds,a1,3-diarylpropane
analogue,2-(3-(3,4-dimethoxyphenyl)propyl)-5-methoxyphenol (3p), displayed the most significant
inhibitory effects against NO production. Further mechanism studies showed 3p is capableof inhibiting iNOS expression in LPS-induced RAW264.7 cells via attenuation of NF-κB
signaling by ERK, p38, and JNK.

26PA-pm025

26PA-pm028

Multiple Activities of Punica granatum Linne against Acne Vulgaris○ Chia-Jung LEE1, Lih-Geeng CHEN2, Wen-Li LIANG3, Ching-Chiung WANG1,3,4（1PhD
Program for Clinical Drug Discovery of Chinese Herbal Medicine, College of Pharmacy, Taipei
Medical University, 2Department of Microbiology, Immunology and Biopharmaceuticals,College of Life Sciences, National Chiayi University, 3School of Pharmacy, College of Pharmacy,
Taipei Medical University, 4Orthopedics Research Center, Taipei Medical University Hospital）

New Bafilomycins Produced by a Streptomyces sp. Isolated from a Marine
Sponge Theonella sp.
Yu-Hsin CHEN1,2, ○ Ping-Jyun SUNG2,3（1Department of Life Science andGraduate Institute of Biotechnology, National Dong Hwa University, 2National
Museum of Marine Biology and Aquarium, 3Graduate Institute of Marine
Biology, National Dong Hwa University）【Aim】The organic extract of the bacterium Streptomyces sp. GIC10-1 isolated from amarine sponge Theonella sp. exhibited significant cytotoxicity toward the K562 humanchronic myelogenous leukemia cell (IC50=0.21 g/mL).
【Methods】The bacterium strain was identified on the basis of 16S rDNA gene sequence.
Bafilomycin type compounds were obtained thought bioassay-guided fractionation. The
structures of isolates were established by spectroscopic methods and the cytotoxicity of thecompounds were determined using a MTT cell proliferation assay.
【Results & Discussion】 Two new 16-membered macrolides, bafilomycins N (3) and O(5), along with three know compounds, bafilomycins M (2), K (1) and JBIR-100 (4), were
produced from Streptomyces sp. GIC10-1. Bafilomycin M (2) was found to exhibit
significant cytotoxicity toward K-562, HL-60, SUPT-1 and LNCaP tumor cells.
25

O

24

22

R3

21

23
20

1

O
19

R2

OH
18

17

2

3

4

OH
5

6

7

O
16

Synthesis and biological evaluation of chalcone, dihydrochalcone, and1,3-diarylpropane analogues as anti-inflammatory agents○ Hsin-Yi HUNG1, Mopur Vijaya Bhaskar REDDY1, Ping-Chung KUO1, Guan-Jhong HUANG2,
Tian-Shung WU1（1School of Pharmacy, National Cheng Kung University Hospital, College ofMedicine, National Cheng Kung University, 2School of Chinese Pharmaceutical Sciences andChinese Medicine Resources, College of Pharmacy, China Medical University）

Development of dual inhibitors of HDAC 6 and β -amyloid (A β ) aggregation○ Chun-Yung CHEN1, Cheng-Chung YEN1, Wei-Jan HUANG1,2（1Graduate
Institute of Pharmacognosy, Taipei Medical University, 2Ph.D Program for theClinical Drug Discovery from Botanical Herbs, Taipei Medical University）【 Aim 】 Histone deacetylases (HDAC) that contain eighteen isoforms control theacetylation of histone to regulate the epigenetic process. Of these isoform enzymes,
HDAC 6 is associated with tubulin acetylation, suggesting it may be a drug target to treat
neurodegenerative disorders. Additionally, amyloid (Aβ) aggregation is a leading cause of
Alzheimer’s disease. To explore the potential anti-Alzheimer’s disease agents, this study
develops dual inhibitors of HDAC 6 and β-amyloid (Aβ) aggregation.
【Methods】In this study, we synthesized a novel series of compounds (5a-5i). Most
compounds were evaluated for HDAC6 inhibitory activity as well as other isoforms.
Furthermore, they were investigated the ability for inhibiting Aβ1-42 aggregation using
thioflavin T (ThT) fluorescence assay.
【Reaults and Discussion】Some compounds showed more potent HDAC 6 inhibitory
activity than did SAHA, a clinically used HDAC inhibitor. Notably, compound 5c
exhibited the highest activity with the IC50 value of 34 nM. Moreover, in the ThT assay,
compounds 5c at the concentration of 20 μM significantly inhibited Aβ1−42 aggregation. In
conclusion, these results indicated that compound 5c has the potential to be developed forthe agent against Alzheimer’s disease.

8
15

14

13

12

11

10

9

R1

Theonella sp.

Streptomyces sp.
strain GIC10-1

Bafilomycin K (1):R1=OCH3, R2=R3=OH
Bafilomycin M (2):R1=R2=OCH3, R3=OH
Bafilomycin N (3):R1=CH3, R2=R3=OH
H
JBIR-100 (4):R1=OCH3, R2=OH, R3=OC(O)C=CC(O)OHH
H
Bafilomycin O (5):R1=CH3, R2=OH, R3=OC(O)C=CC(O)OHH– 87 –

26PA-pm031

26PA-pm058

Cadinane-Type Sesquiterpenes from Chamaecyparis obtusa and Their
Antiausterity Activity○ Dya Fita DIBWE1, 上田 純也 2, 松本 欣三 1, Suresh AWALE1（1Instituteof Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194,
Japan., 2Faculty of Pharmaceutical Sciences, Hiroshima International University,
5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.）

Secondary Metabolites and Biological Activities from the Soft Coral Sinularia flexibilis○ Jyh-Horng SHEU1,2,3, Chia-Hua WU1, Tzu-Zin HUANG1, Tsong-Long HWANG4（1Department of Marine Biotechnology and Resources, National Sun Yat-sen
University, 2Graduate Institute of Natural Products, Kaohsiung Medical University,
3
Frontier Center for Ocean Science and Technology, National Sun Yat-sen University,
4
Graduate Institute of Natural Products, College of Medicine, Chang Gung University）

Pancreatic cancer is one of the most aggressive types of cancer that has the lowest
five-year survival of 5 %. Despite the continual advancement in theurapeutic approaches, noearly methods of detection are available at present; almost all the patients die within a shorttime after diagnosis due to rapid mestastasis. Human pancreatic tumors survive under extreme
nutrient-deficient conditions referred as austerity. Therefore, the discovery of agents that
retards the tolerance of cancer cells to nutrient starvation represent a novel approach inanticancer drug discovery.[1] In our continued effort on the discovery of natural anticancer
agents by employing “anti-austerity strategy”, we recently observed that the chloroform extractof the hinoki ( 檜 ) preferentially killed the human pancreatic cancer cell lines innutrient-deprived medium without causing toxicity in the normal nutrient rich condition.
Phytochemical investigation on this extract led to the isolation of nine compounds, including
two new germacrane-type sesquiterpenes. All of these compounds showed different degree ofpreferential cytotoxicity against six different human pancreatic cancer cell lines (PANC-1, Mia
PaCa-2, KLM-1, NOR-P1, CAPAN-1 and PSN-1). Among these, α-cadinol displayed the mostpotent preferential cytotoxic activity in all the tested cell lines. Furthermore α-cadinol was
found to inhibit the activation of serine/threonine protein kinase B (PKB), also known as Akt.
It is a pro-survival factor that is activated in many tumor types including pancreatic cancer.
Once Akt is activated, it modulates many cellular activities such as cell cycle progression andabnormal proliferation, migration, invasion and angiogenesis. Therefore, inhibitors of Akt
pathway are attractive candidates in cancer therapy.[2] In this study, α-cadinol at theconcentration of 50 µM completely inhibited Akt activation within 3 hours by blocking thephosphorylation at Ser473. Therefore, cadinane-type sesquiterpenes and its analogues may be a
structural template worth exploiting for anti-pancreatic cancer drug development.

Five new cembranolide-related compounds, flexibilisin D (1), secoflexibilisolides A andB (2 and 3), flexibilisolides H and I (4 and 5), along with ten known compounds (6–15) wereisolated from the EtOAc extract of a Taiwan soft coral Sinularia flexibilis. The structures of
all compounds were established by spectroscopic analysis, including IR, MS and NMR data.
The cytotoxicity of compounds 1, 3–15 against the P-388 (murine leukemia), K-562 (humanerythromyeloblastoid leukemia) and HT-29 (human colon adenocarcinoma) cancer celllines were assayed, and the results showed that compounds 7, 10 and 11 revealed significant
cytotoxicity against these cell lines with IC50 values ranging from 6.9 to 16.0 μM.
Compound 11 was also found to display anti-inflammatory activity of reducing superoxideanion generation and elastase release with IC50 values 10.8 and 11.0 μM, respectively.

1)
2)

8

Chemical Constituents of Citrus hystrix and Their Antiausterity Activity
against the PANC-1 Human Pancreatic Cancer Cell Line○孫 思嘉 1, Dya Fita DIBWE1, Ampai PHRUTIVORAPONGKUL2,
Suresh AWALE1（1Institute of Natural Medicine, University of Toyama, Japan,
2
Faculty of Pharmacy, Chiang Mai University, Thailand）
Cancer is the leading cause of death worldwide. Each day, an estimate of 20,000
people dies due to cancer throughout the world. It is expected to be double by the year
2030. So, the battle against cancer has not been successful yet. Among all the forms ofcancers, pancreatic cancer has the lowest 5-year survival rate of less than 6%. Each year,
an estimated number of 30,000 patients die due to pancreatic cancer in Japan. It ranks the
4th and 5th leading cause of death for the female and male cancer patients in Japan. Almost
all the patients with this disease die within a short period after diagnosis. Until now there
is no effective chemotherapeutic agent for this disease. [1-3] In our continued effort on the
discovery of natural anticancer agents by employing “antiausterity strategy”, we recently
screened twenty-two Thai indigenous vegetables and condiments from Chiang Mai
province for their preferential cytotoxicity activity against PANC-1 human pancreaticcancer cell lines under the condition of nutrient-deprived media (NDM). Among the tested
extracts, seven of them exhibited promising preferential cytotoxic activity on PANC-1 in
NDM with PC50 value < 10 μg/mL. The dried fruit peel of Citrus hystrix DC. was found tobe the top two most potent with PC50 value of 1.13 μg/mL. The dried powdered fruit peelsof Critrus hystrix DC. were macerated with 70% EtOH to give a hydro-alcoholic extract
which was further partitioned with hexane to obtain hexane extract. The hexane extract
was chromatographed on silica gel CC using a n-Hexane-EtOAc solvent system with
MPLC to give 6 fractions. Phytochemical investigation on this extract led to the isolationof seven compounds including five geranylated and two prenylated furanocoumarins. In
this presentation, the chemical constituents of this active extract and their preferential
cytotoxicity activity are discussed.

H 19

1

4
18

20

MeO

12

15

O
8
17

19

O

12

O
16

OAc
OOH

O

15
1

O
17

O

OAc

HOO
O

O
18

Flexibilisin D (1)Flexibilisolide H (4)

O

O

R2

Flexibilisolide I (5)

OH
O

O

R1

O
11-Dehydrosinulariolide (7)R1 + R2 = O
11-Epi-sinulariolide acetate (10) R1 = H, R2 = OAc
Sinulariolide (13)R1 = OH, R2 = H

Awale, S., et al. Cancer Res. 2006, 66, 1751–1757. 	
 Ueda J., et al. Des. Dev. Ther. 2014, 8, 39–46.

26PA-pm032S

20

O

14-Deoxycrassin (11)26PA-pm059

Flaccidoxide-13-acetate, extracted from the cultured soft coral Sinularia
gibberosa , reduces the cell migration and invasion of human bladder cancer
through reducing the activation FAK/PI3K/AKT/mTOR signaling pathways
Guo-Fong DAI1, ○ Yu-Jen WU2（1Graduate Institute of Biotechnology, National
Pingtung University of Science and Technology, 2Department of Biological
Science and Technology, Meiho University）
There are many major causes of cancer death including metastasis of cancer.
Flaccidoxide-13-acetate, an active compound isolated from the cultured soft coral Sinularia
gibberosa was examined for the potential anti-cell migration and invasion effects on bladdercancer cells. However, the anti-migration and invasion effects and molecular mechanism of
flaccidoxide-13-acetate on bladder cancer remain poorly understood. In this study, first
discovered that flaccidoxide-13-acetate provided a concentration-dependent inhibitory
effect on the migration of human bladder cancer cells by trans-well migration and invasion
assays. Furthermore, after treatment with flaccidoxide-13-acetate for 24 hours, there wassuppressed the protein levels of matrix metalloproteinase-2 (MMP-2), matrix
metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA) in RT4 andT24 cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1)
and metalloproteinase-2 (TIMP-2) were increased in a concentration-dependent manner.
Further investigation revealed that flaccidoxide-13-acetate suppressed the expression of thephosphorylation of FAK/PI3K/AKT/mTOR pathways. In the present study, we investigated
the anti-migration and invasion effects and underlying mechanisms of
flaccidoxide-13-acetate in RT4 and T24 bladder cancer cells.

1) Awale S., et al. Cancer Res. 2006, 66, 1751−1757.
2) Awale S., et al. Bioorg. Med. Chem. Lett. 2006, 16, 581−583.
3) Ueda J., et al. Drug Des. Dev. Ther. 2014, 8, 39−47.

26PA-pm057

Chemical Compositions from Cultured Products of the Culinary-Medicinal
Honey Mushroom, Armillaria mellea○ Kun-Ching CHENG1, Young-Ji SHIAO2, Tsong-Long HWANG3,
Tian-Shung WU4（1Taiwan Sugar Research Institute, 2Division of Basic Chinese
Medicine, National Research Institute of Chinese Medicine, 3Graduate Instituteof Natural Products, Chang Gung University, 4School of Pharmacy, National
Cheng Kung University）
Armillaria mellea is a traditional well-known fungus which is symbiotic with Chinese
medicinal herb, Gastrodia elata. In this study, more than sixty compounds were isolated
from the MeOH extract of A. mellea fermentation cultured products and havedemonstrated the presence of different groups of organic compounds, including
carbohydrates, fatty acids, sterols, sesquiterpenes, diterpenes, indoles, adenosine
derivatives, and many other components. Among the isolates, CHH-4, CHH-5, CHH-5-2,
CHH-6-5, CHH-7-2 and CHH-8-2 exhibited potent inhibitory activities (IC50 <1.77–7.36
μg/mL) on human neutrophil releasing superoxide anion generation. CHH-4, CHH-5,
CHH-5-2, and CHH-7-2 inhibited fMLP/CB-induced elastase release with IC50 values <2.21–8.54 μg/mL. In addition, the neuroprotective activity results demonstrated that
CHH-8-2 would significantly protect cortical neurons against Aβ(25-35)-mediatedneurotoxicity at 10 μM.

26PA-pm060

Scalarane Ssesterterpenes from a Marine Sponge Hippospongia sp. and Their
Anticancer Activity○ Jui-Hsin SU1,2, Yu-Cheng CHEN1,2, Mei-Chin LU1,2（1Graduate Institute ofMarine Biology, National Dong Hwa University, 2National Museum of Marine
Biology and Aquarium）
One new scalarane sesterterpene, hippospongide C (1) along with four known compounds(2–5) were isolated from a sponge Hippospongia sp., collected off the coast of Taitung,Taiwan. The structures of those compounds were elucidated by analysis of HRMS and 2-D
NMR spectra. The cytotoxicity of compounds 1–5 against three human leukemia cell lines(K562, Molt-4 and HL-60) was also investigated. The results showed that compound 2(heteronemin), the most potent of compounds 1–5, exhibited cytotoxicity against K562,
Molt-4 and HL-60. So far, these are not many studies to evidence anticancer effect ofheteronemin (2). First, the results of antiproliferative MTT assay, and the annexin V-FITC /PI apoptotic assay, indicated that the Molt 4 cell line is the most sensitive one towards
heteronemin. Apoptosis-induced by heteronemin were supported with DNA ladderformation, caspases -3, -8, and -9 activation as well as PARP cleavage. It also induced ROS
generation, and disruption of mitochondrial membrane potential analyzed by flow
cytometry. Using the cell-free system further suggested that heteronemin could be as a
Topoisomerase Ⅱ catalytic inhibitor, unlike clinical anticancer drug, etoposide, as a
Topoisomerase Ⅱ poison. In addition, pre-treatment with ROS scavenger, NAC,
attenuated the apoptosis- and disruption of mitochondrial membrane potential-induced byheteroneminthe about 40% and 49%, respectively. Therefore, heteronemin could be
potential to be effectively anticancer drug candidate.

– 88 –

26PA-pm061

26PA-pm108

Four new Sesquarterpenes (C35), Cryptoterpenes A-D, from the bark of
Cryptomeria japonica○ Yueh-Hsiung KUO1, Hui-Chi HUANG1, Cheng-Chi CHEN2, Chi-I CHANG3（1Department of Chinese Pharmaceutical Sciences and Chinese Medicine
Resources, China Medical University, 2Department of Chemistry, National
Taiwan University, 3Department of Biological Science and Technology, National
Pingtung University of Science and Tchenology）

Prescribing patterns of Wu Lin San alleviates Cyclophosphamide-induced rat
hemorrhagic cystitis○ Jia-Feng XU1, Steven Kuan-Hua HUAN2, Ching-Chiung WANG1（1School of
Pharmacy, College of Pharmacy, Taipei Medical University, 2Division of Urology,
Department of Surgery, Chi Mei Medical Center）【 Aim 】 The prescribing patterns of Wu Lin San (WLS) were explored bycyclophosphamide (CYP) model and discussed the WLS clinical using. 【Method】 We
used the National Health Insurance data of Taiwan (2007-2011) to analyze the clinicalapplication and the principle clinical use of WLS. CYP-induced Sprague-Dawley (SD) rat
were treated by prescribing patterns of WLS and analyzed protein-urine and occult
blood-urine. 【 Result 】 WLS was most prescribed in cystitis (ICD-9-CM 595),
approximately 21.60% that a total of 20362 prescriptions were cited, based on 4398
prescriptions of WLS in cystitis. And the prescription derived 5 type according tofrequency : 1. WLS added with Pa Cheng San (PCS 八正散) and Ti Tang Tang (TTT 抵當湯) 35.11%, 2. WLS with PCS and Tao Ho Cheng Chi Tang (THCCT 桃核承氣湯)
8.46%, 3. WLS with PCS and Dandelion (蒲公英) 7.20%, 4. WLS with PCS 4.15%, 5.
WLS only 2.1%. According to the results, it can prove WLS’s major indication is cystitis
and usually combined with PCS more 55.0% using. SD rats after administration of type1-5
for 4 hours and 6 hours, and their urine were collected in metabolic cages. The results
showed urinary volume were no significant difference in each group. CYP (150 mg / kg
intraperitoneal) induces hemorrhagic cystitis for 18 hours, and oral administration of type
1-5 for two days. According to the results, prescription of Type 2 and 4 reduced theprotein-urine level after one day, as well as type 2,3,4 and 5 reduced the occult blood-urine
level after two days, which type 2 was the most significant improvement. 【Conclusion】
WLS and PCS in the same prescription can reduced the level of protein-urine and occult
blood-urine, and added with THCCT, the effect would be increased.

Cryptomeria is a genus of conifer in the cypress family Cupressaceae; it includes only
one species, Cryptomeria japonica D. DON. It is endemic to Japan, where it is known as
Sugi (Japanese cedar), the national tree of Japan. The wood is scented, reddish-pink incolor, lightweight but strong, waterproof, and resistant to natural decay. It is favored inJapan for a wide range of construction works as well as for interior paneling and otherusage. Because of its industrial importance, the constituents of the leaves and heartwoodof C. japonica including terpenoids have been actively investigated by many researchgroups. According to the literature, the components of this plant have showed various
activities such as antifungal and cytotoxic activities. In the continuing phytochemical
investigation on C. japonica, we further identified four new sesquarterpenes (C35),
cryptoterpenes A-D (1-4) and three known sesquarterpenes (5-7) from the MeOH extractof the bark and the structural determination of these substances using extensive
spectroscopic methods. In this symposium we described the structural elucidation of 1, 2,
3 and 4. Biological activity was in progress.

26PA-pm106

26PA-pm109

High turnover rate of baicalin, a suitable marker substance from Scutellaria
baicalensis in Huang-Chin-Tang○ Li-Ying HUANG1, Li-Geeng CHEN3, Chia-Jung LEE2, Chua-Jung CHANG4,
Ching-Chiung WANG1,2,4（1Graduate Institute of Pharmacognosy, Taipei Medical
University, 2Clinical Drug Discovery from Botanical Herbs, 3Department ofMicrobiology, Immunology and Biopharmaceuticals, National Chiayi University,
4
School of Pharmacy, Taipei Medical University）

The synergistic effect of magnesium and static magnetic field on enhancing
the osteogenesis of dental pulp stem cell
○ Yu-Xuan HUANG1, Kuen-Yu HUANG1, Wei-Zhen LEW2, Haw-Ming HUANG2（1Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei
Medical University, 2School of Dentistry, College of Oral Medicine, Taipei
Medical University）【Aim】Static magnetic field (SMF) and magnesium ion have been widely reported topromote both proliferation and differentiation of various mesenchymal stem cells except
dental pulp stem cell (DPSCs). In this study, we investigated the bio-effects of magnesium
ion and SMF co-treating on DPSCs.
【Method】
DPSCs were isolated from premolars of healthy adults and identified the stemness by flow
cytometry with various specific surface markers. The multipotency of the DPSCs was
confirmed by Alizarin Red S, Safranin O and Oil Red O staining, respectively. The
co-effect of Mg2+ coupled with SMF was evaluated by culturing DPSCs in medium
containing 50 ppm Mg2+ and exposed to 0.4T SMF. The MTT assay and real-time PCR
was used to check the cell viability and osteogenesis related genes, respectively.
【Result】The proliferation rate of DPSCs was significantly increased in medium
containing 50 ppm Mg2+. However, the viability increased slightly if DPSCs co-treatedwith Mg2+ and SMF. The DPSCs showed lower proliferation rate than control whenco-treatment with Mg2+ and SMF. However, the mineralization of calcium deposition was
significantly higher than control group. Although Mg2+ and SMF co-treatment will
decrease the proliferation rate of DPSCs, it will accelerate the osteogenic differentiation of
DPSCs.
【Conclusion】We suggested magnesium and static magnetic field co-treating on dental
pulp stem cell can promote osteogenic differentiation.

26PA-pm107【Aim】Huang-Chin-Tang (HCT) is the fundamental used in traditional Chinese medicine(TCM) for the purposes of cognitive health and treating diarrhea as well as longevity. The
composition of HCT is Scutellaria baicalensis, Glycyrrhiza uralensis, Paeonia lactiflora
and Ziziphus jujube. Based on Taiwan Herbal Pharnacopeia (THP), the maker substanceseach herbal drugs are prescribed. Such as, baicalin of S. baicalensis(SB), glycyrrhizin of G.
uralensis(GU), and paeoniflorin of P. lactiflora(PL). However, there is no rule to choose
which ingredient could be a good marker substance. We use the turnover rates of thesecomponents to investigate the suitable marker substance in HCT.
【Method】According the THP to extract the major component in these three medicinal
slices. Besides, follow the regulation of standard decoction, extracted HCT, SB, GU, andPL by boiling water(TCM-decoction). HPLC-PDA system was used to analysis the major
components.
【Result】 The turnover rates of baicalin, glycyrrhizin and paeoniflorin from raw material
to decoctions were 68.81±2.5%, 62.45±9.4% and 80.86±23%, respectively. And the rates
in HCT were (HCT decoction/SB, GU or PL) 114.02%, 60.49% and 96.73%The turnoverrate of baicalin and paeoniflorin were higher in HCT than the other major compounds.
Therefore, we suggested that baicalin of SB and paeoniflorin of PL are suitable marker
substances in HCT.

Histomorphometric and transcriptome evaluation of early healing bonetreated with a novel human particulate dentin powder○ Yu-Chih HUANG1, Haw-Ming HUANG2（1School of Dentistry, College of Oral
Medicine, Taipei Medical University, 2Graduate Institute of Biomedical Materials
and Tissue Engineering, Taipei Medical University）【Aim】 Human particulate dentin (HPD) was reported to be an alternative material forbone grafting. However, the mechanism of dentin powder on bone healing at molecularlevel are still unclear. The aim of this study was to assess the histological and molecular
expression of bone tissues grafted with human dentin materials.
【Method】The HPD were prepared to 250-500μm particle size. XRD and EDX were
performed to confirm the crystal structure and surface morphology. Sterilized HPD wereused as grafting materials in the heads of 24 New Zeeland white rabbits Tissues and blood
samples were taken from 12 rabbit for microarray assay at 3, 5 and 7 days. Half animals
were sacrificed after 1, 2, 4 and 8 month and the samples were used for H-E staining andmicro-CT.
【Result】XRD and EDX showed HPD have great similarity in crystal structure andchemical characterization with standard hydroxyapatite. Microarray analysis showed that
vascular development and immune and inflammatory related genes were expressed in theearly healing stage. The gene coding for the IL-1 antagonist, IL1RN, was expressed toinhibit the inflammatory response and activate the CCL2 gene to 2.3 times the normal
level. BMP2, RUNX2, COL1A, and OPN expression were also up-regulated. CCL2
predominated in osteoblastogenesis of the HPD-treated bony defect in the early stage ofhealing.
【Conclusion】HPD accelerated bone regeneration and augmentation. These results
suggested that HPD provided potential as a bone graft resource during the bone healing
process.

26PA-pm110

Fabrication of magnesium ion release membrane using carboxymethyl
cellulose-hyaluronic acid
○ Chia-Jen NIEN1, Hsin-Pei CHIANG1, Kuen-Yu HUANG1, Yu-Chih HUANG2,
Haw-Ming HUANG1（1Graduate Institute of Biomedical Materials and Tissue
Engineering, Taipei Medical University, 2School of Dentistry, College of Oral
Medicine, Taipei Medical University）【Aim】An adhesion barriers is a membrane material used in guided bone regeneration(GBR) to isolate the bone defect from the surrounding connective tissue. However, theconventional materials will cause complications such as incomplete coverage,
non-degradable and rapid degradation. The magnesium is reported to promote bonehealing. Accordingly, the aim of this study was to fabricate a novel GBR membranecomposed of CMC and HA to act as a drug delivery system to release magnesium.
【Method】The CMC-HA membranes were fabricated by mixing different ratio of CMC
and HA as a base with the addition of polyvinyl alcohol to form a film. Tensile strengthand ultra-morphology of the membrane were evaluated using a universal testing machineand scanning electron microscope, respectively. The effect of different magnesium
concentration to cells was evaluated by MTT assay.
【Result】The tensile-strength test showed that the increased addition of HA will enhance
the flexibility of membrane. In contrast, the increasing amount of CMC will enhance therigidity of the membrane. The SEM images indicated that the higher addition of HA, thehigher amount of porous were found on the surface of membrane. In addition, the MG63
viability was found increased in CMC-HA-Mg group than fresh medium control.
【Conclusion】The GBR membrane made of CMC and HA was suggested as a potential
drug delivery system for releasing magnesium ion to promote bone healing.

– 89 –

26PA-pm111

26PA-pm114【Aim】Nowadays, the commercially available implants are almost composed of metals or
polymers. However, the implant made by non-resorbable metal such as titanium will cause
complications or additional surgery to remove it. The aim of this study was to develop anovel PLA-fabricated magnesium implant.
【Method】The PLA embedded magnesium implant was prepared by 3D printer using the
medical grade of PLA material. The pH test was performed to determine the effectivenessof the protected coating of the PLA polymer. The heat transduction pattern was evaluatedwith infrared thermal imager. The implants was ultrasonic-welded into the simulated boneblock (PCF20) which was similar to human bone. The tensile-strength was performed totest the pull-out test of the prepared implant.
【Result】The pH of normal saline was around 7.4 during 3 month of testing. The
high-purity magnesium was showed 9.64 to 10.28 of pH value during testing. In contrast,
the PLA-embedded magnesium group showed 5.63 to 6.39 of pH value. It demonstrated
the PLA coating was capable to reduce the degradation of magnesium. The pull-out test
showed that the maximum force was 11 kgf in PLA embedded magnesium group, whichwas 3 times higher than PLA control (maximum 3.7 kgf).
【 Conclusion 】 The PLA-embedded magnesium implant possess the advantage of
biodegradable, good material property and time-saving, which was suitable for any kindsof surgery in clinical.

【Aim】Oxaliplatin, an third-generation platinum-based chemotherapeutic agent, will
induce an intractable peripheral neuropathy in cancer treatment which can not be relieved
with good remedy. Therefore, we wanted to develop the traditional Chinese medicine(TCM) that might reduce the side effects of oxaliplatin. We analyzed the Taiwan National
Health Insurance Research Database, and found Kuei Pi Tang as a good adjunctive TCM
can reduce the risk of death in patients with cancer. Therefore, we exported the prevention
effects of Kuei Pi Tang by Oxaliplatin-induced neuropathy in rats model.
【Method】Adult male Sprague–Dawley rats each received a total of two doses ofoxaliplatin (4 mg/kg, i.p.), injected at 3-day intervals to induce painful peripheral
neuropthy. At the same time 50 mg/kg and 250 mg/kg Kuei Pi Tang were continuous
administered 12 days to evaluate the adverse event-protective activity. Body weight,
mechanical allodynia, cold allodynia were evaluated on days before oxaliplatin
administration and one day before sacrifice.
【Result】Kuei Pi Tang could ameliorate the severity of oxaliplatin-induced mechanicalallodynia and cold allodynia. Therefore, we suggested Kuei Pi Tang could be developed as
an adverse event-protective remedy. In the future, we will explore the adverse
event-protectivemechanisms of Kuei Pi Tang.

26PA-pm112

26PA-pm115

Fabrication and mechanical property test of biodegradable PLLA-embeddedmagnesium bone screw○ Guan-Wei ZHANG1, Yu-Chih HUANG2, Haw-Ming HUANG1（1Graduate
Institute of Biomedical Materials and Tissue Engineering, Taipei Medical
University, 2School of Dentistry, College of Oral Medicine, Taipei Medical
University）

Chemopreventive effects of Kuei Pi Tang on Oxaliplatin-induced neuropathy
in rats
Shih-Han CHEN1, Chia-Jung CHANG1, Her-Shyong SHIAH2,○ Ching-Chiung WANG1,3（1School of Pharmacy, Taipei Medical University,
2
Internal Medicine, Oncology, Taipei Medical University Hospital, 3Graduate
Institute of Pharmacognosy, Taipei Medical University）

The correlation with Ge Gen Tang pattern and common cold: the retrospective
study○ Pei-Ying CHOU1,2, Chen-Jei TAI1,2, Shu-Chen CHIEN3, Ching-Chiung WANG1,3（1Graduate Institute of Pharmacognosy, Taipei Medical University, 2Departmentof Traditional Chinese Medicine, Taipei Medical University Hospital, 3School of
Pharmacy, College of Pharmacy, Taipei Medical University）【Aim】The purpose of this research was to evaluate the symptoms of common cold
patients after using Ge Gen Tang, and analyzed the common cold syndrome type of
Traditional Chinese Medicine (TCM) according to the symptoms of western medicine
through a retrospective study to confirm the most suitable clinical application of Ge Gen
Tang (葛根湯)【Method】This study was a retrospective study. Adult 20 to 65 years of age and Ge Gen
Tang (葛根湯) prescription for treating the common cold (ICD-9-460) were enrolled.
Pregnant woman and combined use western-style cold medicine for treating common cold
were excluded. The primary outcome of this study was the degree of symptoms after
treatment.
【Result】Among the 30 enrollees, 29 were included in the analyses. The severity of cold
symptoms after treatment: nasal congestion, cough, runny nose, sneezing, sore throat,hoarseness, stiff shoulder, chills, general malaise were significantly different. Ge Gen
Tang(葛根湯) could alleviate the wind cold symptoms of the common cold such as cough,runny nose, and stiff shoulder. Furthermore, Ge Gen Tang(葛根湯) combined with Ma
Huang Fu Zi Xi Xin Tang(麻黃附子細辛湯) could alleviate the wind-cold headache, Ge
Gen Tang with Qiang Huo Sheng Shi Tang( 羌 活 勝 濕 湯 ) could alleviate thewind-dampness headache, Ge Gen Tang with Jie Geng(桔梗) could alleviate throat pain,
and Ge Gen Tang with Kan Chiang(甘草) and Xin Gren(杏仁) could alleviate cough.

26PA-pm113

Prescribing Patterns of Ban-Xia-Xie-Xin-Tang alleviate ethanol-induced rat
gastric mucosa cell damage○ Pin-Chen HUANG1,2, Tsung-Hsiu WU1,2, Ching-Chiung WANG1,3（1Graduate
Institute of Pharmacognosy, Taipei Medical University, 2Department ofpharmacy, Taipei City Hospital, 3School of Pharmacy, College of pharmacy,
Taipei Medical University）【Aim】 Ban-Xia-Xie-Xin-Tang(BXXXT), originally documented in "Shang Han Lun", isa herbal formula widely prescribed for digestive diseases. Throughout East Asia, Chinese
herbal products (CHPs) is a widespread form of medical care. Since the co-prescription of
CHPs is popular in Taiwan which utilization way is different from other countries, we
explore the common prescribing patterns of Ban-Xia-Xie-Xin-Tang from CHP claims
database and design bioactive assay to elucidate their effects.
【Method】 To begin with, we found that BXXXT prescribed for disorders of function of
stomach (ICD-9-536) most in Taiwan National Health Insurance Research Database(2007-2011). Next, BXXXT in the use of ICD-9-536 was determined to access prescribing
patterns. The gastroprotective effects of five common prescribing patterns were measuredin ethanol induced primary culture rat gastric mucosal (PRGM) cell damage model.
【Result】 About BXXXT for ICD-9-536, we found five common prescribing patterns:(1)BXXXT only, (2)BXXXT with Ping-Wei-San(PWS), (3)BXXXT with
Xiang-Sha-Liu-Jun-Zi-Tang(XSLJZT),(4)BXXXT
with
Bao-He-Wan(BHW),
Fu-Ling(FL), Yan-Hu-Suo(YHS), and (5)BXXXT with An-Zhong-San(AZS). Of theseseven water extracts, AZS exerted a strong cytotoxic effect in PRGM cells at 50µg/mL
while others did not show obvious cytotoxicity at more than 400µg/mL. However,BXXXT, PWS, XSLJZT, BHW, FL could enhance cell viability in a dose-dependence
manner. The ethanol-induced PRGM cell death model was established in this study. We
would like to further measure their protective effects and perform antibacterial assay tocompare effects of five prescribing patterns.

The Evaluation of Biological Activity of Kai-Lan Extract○ Daih-Huang KUO1, Shu-Yu LI1, Chun-Yann LEE1, I-Li CHEN1, Yi-Jen TSAI1,
Kuo-Cheng WANG1（1Graduate Institute of Pharmaceutical Technology, Tajen
University）
Kai-Lan(Brassica oleracea Linn. Var. Acephala DC.), a member of Brassicaceae vegetables, isrich in bioactive compounds, such as antioxidants, which provide several benefits beyond basic
nutrition and used for chronic diseases. In this study, distilled water and 50% ethanol were used
to extract Kai-Lan respectively, and named for WKAE as white Kai-Lan mass from ethanol
solvent, BKAE as black Kai-Lan mass from ethanol solvent, WKWE as white Kai-Lan massfrom water solvent, and BKWE as black Kai-Lan mass from water solvent. DPPH scavenging
effect, total phenol content, reducing power test and xanthine oxidase inhibition rate were
performed to examine its antioxidant capacities. The total phenol content of WKWE, BKWE,
WKAE, and BKAE(1000μg/ml) were equaled to 61.41, 66.88, 49.00, 59.78 μg of gallic acid.
The xanthine oxidase inhibition rate was 99.46%, 110.13%, 91.44% and 95.62% for WKWE,
BKWE, WKAE, and BKAE (1000μg/ml). In addition, the vasodilation effect were 51.16%,
54.9% and 48.86% for WKWE, BKWE and BKAE respectively in Hcy-damaged model thatindicated these extracts could protecte coronary artery from Hcy-injury. In conclusion, Kai-Lan
extracts exhibit a significant anti-oxidative activity. Furthermore, Kai-Lan also showed asignificant protection effect from Hcy-damage coronary artery even though it gave a poor
performance in coronary artery dilation which might be potential to develop a useful healthy
product in the future. (Acknowledgment: This study was supported by MOST
103-2632-E-127-001)

26PB-am199

English Role-play Using Visual Aids to Enhance Patient Comprehension○池上 小湖 1, 西村 真澄 1, フォン フーワー 1（1京都薬大）Introduction: As the 2020 Olympics approach, we must teach our students how todispense pharmaceuticals to patients who cannot speak Japanese. To ensure foreign
patients receive appropriate care with the correct medications, pharmacists must provide
patients with precise, coherent instructions to achieve successful outcomes. We introduced
English role-play (RP) to nurture communication skills, and the use of visual aids indispensing over-the-counter (OTC) and prescription drugs. Methods: Fourth-year students
were placed in pairs and asked to create illustrations for use as visual aids in both OTC
and prescription drug situations of their choice, together with a role-play script thatincorporated the use of their visual aid. Students were asked to fill in a questionnaire after
their RP performance. Results: Students found that the use of visual aids enhanced thecommunication between pharmacist and patient. It was easier to convey detailed
information on dosage and administration, and to provide clear warnings about potential
adverse reactions and other precautions in use. Aids also served as a memory aid for thosein the pharmacist role, ensuring all necessary information would be provided. Discussion:
Vital drug information must be communicated by the pharmacist during the dispensing ofboth OTC and prescription drugs. The use of visual aids to illustrate important concepts
can be quite effective in overcoming language barriers. Improvements suggested by thestudents included providing copies of the visual aid to the patients along with their drugs.
Further evaluation and input from actual pharmacists may provide guidance on how to
improve the students’ efforts in creating such aids. Most importantly, this practice will
hopefully nurture better understanding towards the challenges for those who do not speak
Japanese and allow students to acquire a more professional attitude as they shoulder their
responsibilities as a member of this helping profession.

– 90 –

26PB-am293

Learning Pharmaceutical Dispensing with Role-Plays○ Foo Wah FOONG1, 池上 小湖 1, 西村 真澄 2（1京都薬大 , 2兵庫県立大）Introduction: Dispensing over-the counter (OTC) and prescription-based (PB)
pharmaceuticals is a challenge for Japanese pharmacists as they need to speak the mostextensively spoken English (even from non-English speaking countries) for professional
practice, especially when the influx of foreign tourists to Japan has reached more than 20
million in fiscal year 2015. We designed a one-semester coursework for year-4 (Yr-4)
students to learn dispensing - both over-the-counter (OTC) products andprescription-based (PB) pharmaceuticals - under various settings via role-plays (RPs) inuniversity B. Methods: Yr-4 undergraduates (n=64) were first taught various
conversational expressions under different OTC and PB settings using a compact disk(CD)-attached textbook. They were then grouped into pairs, and asked to role-playdispensing using OTC and PB settings of their choice. After the RP sessions, students were
given questionnaires to fill out their answers. Results: Based on effective responses(100%) on the survey-day, students playing the roles of pharmacist and customer/patient
found the RPs beneficial, and they scored (mean ranking 1-4) the following factors
accordingly: viz., technical term acquisition (>3), ability to think (>2), write (>2), speak(>2) in English, ability to ask questions (>2) and answer queries (>2), acquisition of basics
in dispensing (>3), etc. Discussion: Proper and comprehensive dispensing of OTC and PB
pharmaceuticals is important for pharmacists to provide the best professional service tocustomers/patients. RPs undertaken by students found the method useful to get first-handexperience on dispensing using English. Based on RP experience, they felt confident tohandle customers/patients at pharmacy/hospital settings.

26PB-pm027

Effect of dietary restriction from old on the levels of Akt1 and mTOR in rat
liver○ Keiko ODERA1, Yi SHANG2, Ramesh SHARMA3, Shizuko KAKINUMA2,
Yoshiya SHIMADA2, Ryoya TAKAHASHI1（1Fac. of Pharm. Sci., Toho Univ.,
2
Dept. of Radiation Effects Research, NIRS, QST, 3Dept. of Biochem., NorthEastern Hill Univ.）【 Aims 】 Dietary restriction (DR) from weaning or young adult stages in rodents
throughout their usual life-span has been shown to prolong longevity and lower or delay
the occurrence of many late-onset diseases. However, the effects of DR performed at
middle age or later have not been well investigated. We previously found that DR initiatedeven relatively late in life can restore animal's youthful conditions. These beneficial effects
of DR might be due to the alteration of insulin/IGF-1 signaling pathway. To examine thispossibility, we investigated the effect of DR initiated from old on the levels of some
protein molecules involved in insulin/IGF-1 signaling pathway.
【 Methods 】 DR was performed by every-other-day (EOD) feeding on weekdays.
Twenty-eight month-old male rats (F344/DuCrjCrl) fed ad libitum (AD) were subjected to
EOD feeding for about 3 months. Four month-old rats fed ad libitum were used as young
AD control. The protein levels of Akt1 and mTOR were determined by an immunoblot
analysis using a specific antibody.
【Results and Discussion】The body weight of the old rats was reduced by about 35% at
the end of the EOD feeding experiment. Decreased weight in the liver was also observedin EOD-fed old rats compared with AD-fed old ones. Total Akt1 level tended to increase in
the liver of EOD-fed old rats compared with AD-fed young ones. No appreciable change
in total Akt1 level was observed by EOD feeding. On the other hand, total mTOR level
was relatively constant in the liver during aging and EOD feeding experiment. The levelsof phosphorylated forms of both proteins are currently under investigation.

26PB-pm146

Cost Analysis for Treatment of Adult Patient in Universal Coverage
Healthcare in Systemic Lupus Erythematosus and Lupus Nephritis in Fiscal
Year 2013 at Srinagarind Hospital, Khon Kaen University, Thailand○ Theera RITTIROD1, Jananya TANABOON1, Phattranit KAMTUO1,
Nungruthai SOOKSAI1, Siraphop SUWANNAROJ2（1Faculty of Pharmaceutical
Sciences, Khon Kaen University, 2Faculty of Medicine Khon Kaen University）
Systemic Lupus Erythematosus (SLE) or Lupus is a disease that the immune
system cannot recognize their tissue. That affect inflammation in various tissue such as
kidney which is called Lupus Nephritis (LN) that cause renal impairment and increasemortality rate. The main pharmacologic treatment of LN are Mycofenolate Mofetil and
Cyclophosphamide that is very high cost drug. The hospital has a responsibility to manage
the fund that was given from National Health Security Office. The objective of this study
is to analyze direct medical cost for treatment in SLE and LN with a Retrospective
Descriptive Study. This study identified 23 patients (14 patients in SLE and 9 patients in
LN). Average patient age in SLE is 32.57 years-old (min 20 years-old, max 60 years-old)and 31.22 years-old in LN (min 18 years-old, max 62 years-old). Average cost oftreatment SLE patients (5,585.57 Baht/person/year; min 440.00 Baht, max 28,808.00 Baht)
was statistical significantly lower than average cost of treatment LN patients (54,805.10
Baht/person/year ; min 600 Baht, max 294,711.00 baht) (p=0.048).The highest cost was
pharmaceutical cost (80.30% in LN, 47.71% in SLE) and diagnosis cost in LN was
statistical significantly higher than SLE (69,315.00 and 20,995.00 Baht p= 0.018). So thehospital has to manage and cut of non-rational cost to minimize hospital cost. Or has
strategies to prevent the aggregation from SLE to LN.
Keywords : direct medical cost, Systemic Lupus Erythematosus (SLE), Lupus Nephritis(LN)

27PA-am014S

A MALDI-TOF mass spectroscopy-based approach to evaluate the cytosolictranslocation efficiency of octaarginine-mediated intracellular protein
delivery○ Jan Vincent ARAFILES1, 川口 祥正 1, Bechara CHERINE2, Illien FRANCOISE2,
河野 健一 1, Burlina FABIENNE2, Sagan SANDRINE2, 二木 史朗 1（1京大化研 ,2
パリ第６大学）[Introduction] Octaarginine (R8) is among cell-penetrating peptides (CPPs) commonlyused in protein therapeutics to aid cellular entry; however, studies to evaluate the cytosolictranslocation efficacy of R8-mediated cellular delivery remain limited. We designed asystem to evaluate this using a conjugate of biotinylated R8 and ubiquitin(Ub-CK[Bio]G4R8). Upon entry, Ub-CK[Bio]G4R8 is cleaved by cytosolic deubiquitinases
liberating the biotinylated-R8 portion. The efficacy of R8-mediated intracellular delivery
is assessed by measuring free biotinylated-R8 amount in cytosolic fractions using
MALDI-TOF MS-based technique [Burlina et.al. Nat. Protoc. 1, 200-205 (2006)].
[Methods] Biotinylated-R8 (CK[Bio]G4R8) and ubiquitin-thioester was prepared by
Fmoc-solid-phase peptide synthesis and IMPACT system (NEB), respectively. Purified
CK[Bio]G4R8 was conjugated to the C-termimus of ubiquitin (Ub-CK[Bio]G4R8) via
native chemical ligation. CHO-K1 cells were treated with Ub-CK[Bio]G4R8, followed bycell lysis in the presence of known amount of internal standard peptide(CK[Bio](2H)G4R8). Free biotinylated-R8 was then isolated using streptavidin beads andquantified by MALDI-TOF MS.
[Results and Discussion] Pyrenebutyrate (PyB) is known to enhance direct penetration of
R8-fused proteins into the cytosol. We employed this system to confirm its applicability
for the quantification of cytosolically liberated R8. Treatment of the cells with
Ub-CK[Bio]G4R8 in the presence of PyB yielded free CK[Bio]G4R8 within the cytosol,and the detection of picomole amounts of CK[Bio]G4R8 was possible. By using thissystem, we were also able to analyze the amount of endocytosed and cytosol-released
Ub-CK[Bio]G4R8. Overall, our system is promising for quantitatively measuring theefficacy of R8-mediated cellular entry.

27PA-am015

Anticancer mechanism of action of palmitoyl piperidinopiperidine○安藤 さえこ 1, 松本 晴年 1, 深町 勝巳 1, 二口 充 1, 酒々井 眞澄 1（1名市大院医）
We examined mechanism of action of palmitoyl piperidinopiperidine, named PPI (patented
in 2014, 5597427). In silico docking simulation exhibited that PPI can bind to SH2
domain of the transcription factor STAT3. PPI markedly inhibited transcriptional activityof STAT3 in HT29 and SW837 human colon carcinoma cells. PPI caused a decrease in
expression levels of pSTAT3 in both whole lysate and chromatin fraction of HT29 cells
without decreasing the expression levels of STAT3. Also, PPI caused a dose dependent
decrease in expression levels of VEGF, Bcl-2, Bcl-XL, and cyclin D1. We found that PPI
decreased the number of blood vessels in the implanted tumors in a mouse xenograftmodel. In chick chorioallantoic membrane assays, we found that PPI caused adose-dependent decrease in number of blood vessels and their branches. Collectively, thedrug PPI we invented inhibits the growth of human colon carcinoma cells by affecting thefunction of molecules that are related to angiogenesis, apoptosis and cell cycle.

27PA-am032

Design and Screening of an o -Substituted Anilide Library for Histone Lysine
Demethylase Inhibitors○ Pattaporn JAIKHAN1, 伊藤 幸裕 1, 鈴木 孝禎 1（1京府医大院医）
Histone lysine methylation has been extensively studied so far. Methylation on histonelysine residues is mediated by two major types of enzyme including histone methyltransferase and histone lysine demethylase (KDMs). KDMs are classified by theirstructures and mechanisms to hydroxylate methyl groups attached to the ε-amino group(Nε) of lysine. One is defined as flavin-dependent amine oxidases. Second is a family ofFe(II) and α-ketoglutarate-dependent enzymes sharing a conserved catalytic domain called
Jumonji C (JmjC) domain-containing demethylase enzymes. Recent studies revealed thatsome of the KDM isoforms are involved in disease sates such as cancer andneurodegenerative diseases. Therefore, development of KDMs inhibitors with subfamily
specificity as well as a favorlable kinetic profile could lead to the identification ofpromising candidates for both chemical probes and therapeutic agents.
The aim of this study is to design and screen the biological activity of an o-substituted
anilide library for KDMs inhibitors by structure-based drug design. The novel KDM
inhibitors are expected to deminish the progression of tumor and neurological disorders.
References:
1. Pilka, ES, et al. Drug Discov Today. 2015 20(6):743–749.
2. Suzuki, T, et al. J Med Chem., 2013 56 (18), 7222-7231.
3. Torres, OI, et al. Nat Commun., 2015 17(6), 6204.

– 91 –

27PA-am099

27PB-am017

Chemical constituents derive from Artocarpus xanthocarpus and their antimelanogenesis mechanism investigation○柯 宏慧 1, 金 語菁 1, 陳 益昇 1（1高雄醫科大 - 高雄醫學大學香粧品學系）

Optimization for Neural Catecholamines, its metabolites and Related Drugs ina Single LC-MS/MS Analysis using API4000○ Andrea Roxanne Jocsing ANAS1,2, 鈴木 弘美 1, 今西 進 2, 原田 健一 2,3, 澤田 誠 1（1名古屋大学環境医学研究所 , 2名城大学薬学部 , 3名城大学大学院総合学術研究科）

Objectives: The aim of this study is to verify the chemical constituents of Artocarpus
xanthocarpus and their molecular biological mechanisms on α-MSH induced melanogenesis incellular model. The authors are looking forward to developing some cosmetic active additives.
Methods: The methanolic extract of A. xanthocarpus was purified by silica gel column
chromatography and the structures of secondary metabolites were spectroscopically determined.
The effects of active compounds on cell viability, melanin content, and tyrosinase activity were
measured in B16F10 melanoma cells. The mechanisms of molecular biology of active
compounds were evaluated by western blot. Results: Eighteen known compounds and six newcompounds were isolated from the roots of A. xanthocarpus. The new compounds included
artoxanthocarpuone A (1), artoxanthocarpuone B (2), hydroxylakoochin A (3),methoxylakoochin A (4), epoxylakoochin A (5), and artoxanthol (6). Among the isolated
compounds, artoxanthol (6), arboctalol (9) steppogenin (11), norartocarpetin (12), resveratrol(19), oxyresveratrol (20), and chlorophorin (21) strongly inhibited mushroom tyrosinase
activity with IC50 values of 5.7, 6.4, 1.9, 0.9, 4.9, 1.0, and 2.5 μM, respectively.
Artoxanthocarpuone A (1), artoxanthocarpuone B (2), methoxylakoochin A (4), lakoochin A(8), cudraflavone C (17), artonin A (18), resveratrol (19), and chlorophorin (21) reduced
tyrosinase activity and inhibited α-melanocytestimulating hormone-induced melaninmechanism of
production in B16F10 melanoma cells and were not cytotoxic. Since thecompounds 1, 12, 16, 17, and 21 involved in the improvement of molecular biology is still
unclear, we investigated the melanin synthesis associated signals by western blot assay, such as
tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase related protein-1(TRP-1), tyrosinase related protein-2 (TPR-2), phospho-cAMP-response element binding
protein (p-CREB), and phosphorylation of mitogen-activated protein kinases (MAPKs)[phospho-extracellular signal-regulated protein kinase (p-ERK), phospho-c-Jun N-terminal
kinase (p-JNK), phospho-p38]. Conclusions: The results suggest the potential utility of A.
xanthocarpus–derived compounds as depigmenting agents.

27PA-am135[Purpose]: The central catecholamine neuron system— dopamine, epinephrine, and norepinephrine— has aunique role in the brain. It has an essential role in the synaptic transmitter metabolism and modes of action in
the psychotropic drugs (Moore and Bloom, 1978). However, most studies in research analyze neural
catecholamines, its metabolites and related drugs separately without realizing the effects of the drugs in thebrain. We have optimized a procedure on how to analyze quantitatively neural catecholamines, its metabolites
and related drugs as an application to our future researches. In this study, we will optimize neural
catecholamines, its metabolites, haloperidol, raclopride, and TSPO ligands PK11195 and FEPPA in a single
liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis using API4000.
[Methods]: Neural catecholamines, i.e. dopamine, epinephrine, and norepinephrine; its related metabolites 3MT, L-DOPA and Tyr; and raclopride were optimized in LC-MS/MS in API4000 using a solvent gradient of
10%MeCN with 0.1% HCOOH from start to 10 min, to 60% MeCN with 0.1% HCOOH for 4.0 mins in a
Wakosil-II 5 C18HG, 2.0x50mm (W) guard column and Inert Sustain C18 peek column, 2.1 x 150 mm withflow rate of 200 μL/min. Designated Q1 (parent ion) and Q3 (daughter ion) were optimized in API4000. A
separate optimization for TSPO ligand PK11195 was done using the same columns. A solvent gradient of 90%
MeCN with 0.1% HCOOH to 100%MeCN with 0.1% HCOOH for 8.0 mins was used for PK11195. These twosolvent gradients were pooled to obtain a neural catecholamines and its metabolites-drug LC-MS system in asingle LC-MS/MS run in 15 mins. Finally, FEPPA was added to this system.
[Results and Discussion]: We analyzed raclopride together with neural catecholamines and its metabolites in
10% MeCN with 0.1% HCOOH from start to 1.0 min, 60% MeCN with 0.1% HCOOH for 4.0 min. Raclopride,
neural catecholamines, and its metabolites eluted at 2.0-3.0 mins. In addition, the final solvent gradient forneural catecholamines, its metabolites, haloperidol, and TSPO ligands PK11195, and FEPPA used 10% MeCN
with 0.1% HCOOH from start to 1.0 min, 60% MeCN with 0.1% HCOOH at 2.0 min to 4.0 min, 90% MeCN
with 0.1% HCOOH at 5.0 min to 100% MeCN with 0.1% HCOOH for 12.0 min. Retention times (tR) of neural
catecholamines eluted at 2.0-3.0 mins, haloperidol at 6.8 min, PK11195 at 10.3 min, and FEPPA at 8.0 min.
Reference: Moore, R. Y., and F. E. Bloom. "Central catecholamine neuron systems: anatomy and physiology ofthe dopamine systems." Annual Review of Neuroscience 1.1 (1978): 129-169.

Learning status of pharmacists belonging to the Ai-Gi (Aichi-Gifu) Block of
MIC Co., Ltd. (Second Survey Report)○森 厚司 1, 山本 有人 1, 山田 隆博 2（1株式会社ミック 岐阜支店 , 2株式会社ミック 名古屋北支店）[Objective] Self-learning of continuously advancing medical information is difficult forpracticing pharmacists. Those working for dispensing pharmacies, in particular, are often toobusy with their routine duties to learn new medical information. Previously, we conducted asurvey regarding how pharmacists in our company balanced learning with routine duties, andreported the results in November 2014. Since then, the number of pharmacists giving academicpresentations has increased. This prompted us to conduct a new survey to investigate howlearning attitudes and the balance between learning and routine duties have improved.
[Methods] We conducted a questionnaire survey using 18 items about the balance between
learning and routine duties, among pharmacists in the Gifu and Nagoya-Kita Branches of ourcompany, and compared the results with those of the previous survey. In addition, we analyzed
the effects of the number of pharmacists and number and unit price of prescriptions in each
pharmacy.
[Results] A total of 57 pharmacists from 17 pharmacies completed this survey (as compared to
53 pharmacists in the previous survey). As in the previous survey, all the pharmacists were
aware of the importance of learning. In total, 63.2% continued to learn (+18.2%), and 57.9%
felt that their frequency of learning was insufficient (-9.1%). Those who found it difficult tocontinue learning because of their busy routine duties indicated that a shortage of pharmacists
affected their learning more than the number and unit price of prescriptions.
[Discussion] The increased number of pharmacists who were able to continue learning despite
their tight work schedules in both branches may be attributable not only to an improved
educational curriculum, but also to the idea of a “health support pharmacy” and “family
pharmacy” advocated by the Ministry of Health, Labour and Welfare. Continued learning has
become even more important since the “family pharmacist” system was introduced in thisyear’s revision of the medical payment system. We plan to continue to support our pharmacists
to maintain their eagerness to learn.

27PB-am030S

Screening of chemical modifications in human skin keratins using on-tapedigestion method○川瀬 士瑛 1, 廣嶋 佑亮 1, 大江 知行 1, 李 宣和 1（1東北大院薬）【Objective】Chemical modifications in proteins can provide significant information
about biological events in the human body. Keratins are the major proteins in human skin.
Therefore, modifications in keratins can be potential biomarkers of skin and/or body
conditions. In our previous studies, an MS-based non-invasive proteomic methodology
was developed using filter-aided sample preparation, and H2O2- and UV-induced
methionine oxidation sites were determined in human skin keratins. Here, we introduce anon-tape digestion as simpler and more efficient sample preparation method for keratin
analysis. Various chemical modifications in human skin keratin were then screened using
the methodology developed.
【Methods】Human skin keratins were obtained non-invasively by tape stripping. After
reduction and carbamidomethylation of disulfide bonds, tryptic digestion was performedon tape. The tryptic peptides were analyzed by LC/ESI-MS and MS/MS. To assess thepossible modification sites in keratins, in vitro chemical modifications were carried out bytreating human skin proteins stripped by tape with glucose, 4-hydroxy-2(E)-nonenal,
4-oxo-2(E)-nonenal and methylglyoxal, followed by on-tape digestion.
【Results & Discussion】The current methodology has improved amino acid sequence
coverage of each keratin detected from human skin as follows; K1 (42.7%→80.1%,
516/644 amino acids), K2 (36.6%→93.1%, 595/639 amino acids), K9 (25.2%→60.0%,374/623 amino acids), and K10 (47.8%→69.7%, 407/584 amino acids). From thereactions between human skin proteins and various reactive chemical species, tryptic
target peptides carrying modification sites were determined such as His372 (K2). Highly
sensitive LC/ESI-SRM/MS method developed for the target peptides will be applied toscreen various chemical modifications in human skin keratins.

27PA-pm117

27PB-am031S

Cadmium (Cd) is nephrotoxic metal that has a number of consequences for renal
function that may stem from its induction of destructive cellular processes. Cells exposed
to Cd may have methods to counteract toxic effects with processes like autophagy.
Autophagy is a homeostatic catabolic mechanism involved in the destruction of misfoldedor dysfunctional proteins and organelles. This study investigated the mechanism of
Cd-induced autophagy and the importance of process on cellular survival under Cd stress.
Treatment of rat mesangial cells (RMC) with Cd markedly induced the formation of
autophagosomes detected by immunofluorescence of CytoID. LC3-II formation andprocaspase3 cleavage were used as indicators of autophagy and apoptosis, respectively.
Cd-induced autophagy was found to be independent of reactive oxygen species, andsuppressed by thapsigargin treatment, suggesting the necessity of intracellular Ca2+. In
RMC treated with a JNK inhibitor, autophagy induced by Cd was inhibited, indicating that
the IRE-JNK pathway may be required for autophagy activation after Cd treatment.
Because autophagy has been reported to protect against Cd-induced cell death,particularly apoptosis, we undertook two strategies to examine the effect of autophagy
deficiency, first by looking at the effect of Cd on mouse embryonic cells from
autophagy-deficient ATG16 knock-out mice (MEF-ATG16-/- cells), and secondly bysilencing ATG16L1 directly in RMC. Cd-induced autophagy was found to be protective
against cell death induced by Cd. The absence/decrease of autophagy resulted in increased
apoptosis in MEF-ATG16-/- cells and ATG16L1-silenced RMC, suggesting that autophagy
plays an important role in cell survival after Cd exposure.

【Objective】Oxidative stress is considered as a major contributor to the age-related
degenerative diseases. The increased production of reactive oxygen species occurs duringoxidative stress and results in the formation of lipid hydroperoxides, which can be
decomposed to reactive aldehydes such as 4-oxo-2(E)-nonenal (ONE). Angiotensin (Ang)II (DRVYIHPF) is the major bioactive peptide that involves in cardiovascular functions.
Our previous studies have demonstrated that ONE modified N-terminal aspartic acid of
Ang II to produce pyruvamide-Ang II (Ang P) and this modification altered the biologicalactivities of Ang II significantly. In the present study, LC/ESI-SRM/MS-based
quantification method was developed for pyruvamide-Ang peptides in plasma to further
understand the effect of lipid peroxidation on the cardiovascular diseases.
【Methods】Analytical methodologies were developed for N-terminal pyruvamide form ofabundant Ang peptides (Ang I, Ang II, and Ang 1-7). Girard’s reagents (GRs) were
employed to derivatize the N-terminal keto group. Conditions for derivatization and twoconsecutive solid phase extraction steps using C18 and weak cation exchange (WCX)
cartridges were optimized. LC-MS conditions and SRM transitions were then optimized.
Internal standards (ISs; [13C5, 15N]-Ang PI, -Ang P, and -Ang P1-7) were prepared.
【Results & Discussion】Ten times increase in MS intensity of Ang PI, Ang P, and Ang
P1-7 was observed after derivatization with GRs at 37 oC for 2 h in 10% acetic acidaqueous solution. The removal of excess GRs by C18 cartridge and a selective isolationof positively charged GR derivatives by WCX allowed to achieve over all recoveries of
87.8–116.9%. The limits of detection were determined to be fmole levels. Stable isotope
dilution LC/ESI-SRM/MS analysis using ISs prepared will be applied to quantify
pyruvamide Ang peptides in human plasma.

Cadmium-incduced autophagy through JNK and Ca2+ in rat mesangial cells○藤代 瞳 1,2, Douglas M. TEMPLETON1（1Department of Laboratory Medicine
and Pathobiology, University of Toronto, 2徳島文理大学薬）

Stable isotope dilution LC/ESI-SRM/MS method for N-terminal pyruvamide
angiotensin peptides in human plasma○池田 真人 1, 横田 涼 1, 大江 知行 1, 李 宣和 1（1東北大院薬）– 92 –

27PB-am093

Paraoxon induces tremor by activating nicotinic acetylcholine receptors inmice○アルベス伊波 イーゴル 1, 國澤 直史 1, 清水 佐紀 1, 尾西 美咲 1, 野村 有治 1,
1 1
松原 菜美 1, 岩井 千紘 1, 小川 瑞葵 1, 橋村 舞 1, 河合 悦子 1, 大野 行弘 （大阪薬大・
薬品作用解析）Paraoxon (POX), a toxic metabolite of parathion, acts as a cholinesterase inhibitor. We
performed behavioral studies to clarify the mechanisms for POX-induced tremor in mice.
POX dose-dependently caused whole body tremor, which was inhibited by mecamylamine(nicotinic receptor antagonist), but not by trihexyphenidyl (muscarinic receptor antagonist).
Expression analysis of Fos protein, a biomarker of neural excitation, showed that POX
region-specifically activated the dorsal lateral striatum (dlST) and inferior olive (IO).
POX-induced Fos expression in the dlST and IO was also blocked by mecamylamine. Our
results suggest that POX provokes tremor by activating nicotinic acetylcholine receptors in
the dlST and/or IO.

27PB-am098

Induction of epileptiform activity and drug responses in cultured human
iPSC-derived neuronal networks using MEA system○小田原 あおい 1,2,3, 鈴木 郁郎 2（1東北大学 , 2東北工業大学 , 3特別研究員）

The functional network of human induced pluripotent stem cell(hiPSC)-derived neurons is a potentially powerful in vitro model for evaluating
disease mechanisms and drug discovery. To evaluate the drug effect in cultured
hiPSC-derived neurons, we used a planar MEA measurement system. Human
iPSC-derived cortical neurons were cultured on 384 multi-electrode arrays(MEAs) chip. We firstly confirmed the modulation of activity by typicalglutamatergic and GABAergic receptor antagonists/agonists in spontaneous
firings and evoked responses. Next, to evaluate the utility of these human
iPS-derived neural networks for modeling human disease states and drug
screening, we examined chemically evoked epileptiform activity.
Electrophysiological seizes were induced by pentylentetrazole (PTZ) and4-Aminopyridine (4-AP), the most widely used chemical convulsant in animalmodels to screen for new anti-epilepsy drugs. We also examined theanti-convulsant effects of two common clinical AEDs, phenytoin and sodium
valproate (VPA). PTZ induced a rapid increase in synchronized burst firings(SBFs) at 100 µM and 1 mM. Phenytoin and VPA also suppressed
PTZ-induced epileptiform activity. From these results, we suggest that thehuman iPSC-derived neuron culture is a useful model system to investigate theeffects of common AEDs and an alternative to animal experiments for drug
screening.

27PB-pm166

Microemulsion formulation optimization for topical application○吴 宝珠 1, Yu-Hsiang LIN1（1高雄医大）
Purpose. The aim of the present study was to design a microemulsion for topicalapplication.
Methods. A mixture experimental design with five independent variables (X1: oil, X2:
surfactant, X3: catechin, X4: cosurfactant and X5: water) was developed, and the response
surface methodology was used to study the effect of formulation components on
physiochemical characteristics and penetration capacity of a drug-loaded microemulsion,and to obtain an optimal microemuslion formulation.
Results. The drug-loaded microemulsions and characteristics were related to many
parameters of the components. The transdermal amount and skin deposition amountincreased about 4.1~111.6-fold and 0.6~7.6-fold respectively. The lag time wassignificantly shortened from 10 h to 1.0~6.7 h. Moreover, the physicochemical
characteristics and drug level of the tested microemulsion did not show significant
degradation after 3 months of storage at 25℃.The drug-loaded microemulsion did notcause significant irritation compared to the water-treated group.
Conclusion. Appropriated microemulsion could be a potential carrier for drug topicalapplication.

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