Madindoline ©

1. Discovery, producing organism and structures1,2)
Madindolines were isolated from the culture broth of Streptomyces nitrosporeus strain K93-0711
and found to be selective growth inhibitors of IL-6-dependent cells (MH-60)1). Madindoline B(3aR, 8aS, 2’S) is a stereoisomer of madindoline A (3aR, 8aS, 2’R)2,3).
HOHO
3aR

N
O

8aS

N

H
CH3O
2'RO

CH3H3C

Streptomyces nitrosporeus K93-0711

3aR

O8aS

HCH3O
2'SCH3H3C

Madindoline AOMadindoline B

2. Physical data (Madindoline A)2)Light yellow needles. C22H27NO4 ; mol wt 370.20. Sol. in MeOH, EtOH, CHCl3. Insol. in hexane.
120
100
Cell growth (%)

3. Biological activity1)
1) Growth inhibition of the IL-6-dependent MH60 cells
Madindolines A and B (MDL-A, B) showed potent
growth inhibitory activity against IL-6 dependent MH60
cells with IC50 values of 8 and 30 µM, respectively.
Madindolines did not show anti-microbial or cytocidal
activity at 1000 µg/ml and 100 µg/ml, respectively.

80
6040 IL-6-dep.MH60;MDL-A,20;MDL-BIL-6-indep. MH60;MDL-A,;MDL-B

0110Dose ( M)1002) Selectivity of madindoline A
Selectivity against some cytokines was examined in cytokine-dependent or -sensitive cell lines.
MDL-A inhibited growth of IL-6 dependent MH60 cells at 68 µM, but did not influence othercytokine activity.
100MDL-A0 M
68 M

Cell growth (%)

80
60
4020Cytokine
Cell line

0IL-2
CTLL-2

IL-3
G-CSF
Baf/GCSFR-gp130

IL-6MH60

TNF (+) TNF (–)
L9293) Inhibitory mechanism of madindoline A5)
IL-6 has three topological binding sites (sites I, II, and III), and gp130 has two binding sites (sites
1 and 2)(29, 30); IL-6 first binds to the IL-6 receptor (IL-6R) at site I, IL-6 then binds to site I of
the first gp130 at site II, forming a trimeric IL-6/IL-6R/gp130 complex. The trimeric complex
then induces homodimerization of gp130 and forms a hexameric complex, activating the JAK/STAT signal transduction cascade.
MDL-A binds to gp130 and inhibits actions of IL-6 without inhibiting formation of the trimericcomplex. Therefore, the MDL-A mechanism of action involves binding to gp130 site 2, the sitefor IL-6 site III, and inhibiting gp130 homodimerization, resulting in inhibition of IL-6 activity.

4. Madindoline A is commercially available as biological reagent.
5. Total synthesis
The total syntheses of madindolines have been reported by several groups. Below are threeschemes achieved by Ōmura’s group (See Appendix-I).
1) First total synthesis3,6)
H 3C

CHON
H 3CCl1) n-Bu2BOTfOOOH89%2) MeONa 87%OCH 3CH 3

MeO 2CHOCH 3OCH 31) Bu 2CuLi;
PhSeBr2) H 2O2, AcOH
3) RhCl 3
73% for 3 steps

OOMeOH

LiHMDS (2 eq.)
H 3C

CHO97%

MeO 2CN2) TESCl, Et 3N 88%

HOH 3CPCy 3RuPhPCy 3

MeO 2C
HOCH 3 Grubbs 1st reagent
69%

CH 3

OHCH 31) TBSOTf 74%2) MnO 2 100%OTBS
MeO 2C
TBSO

CH 3
O
CH 3

H 3C

1) NaBH 4, CeCl 3 80%
2) TBSCl, KH 92%

CH 3OH
CH 3

CH 3
OTBSHOTBSO

3) DIBAL-H 100%

CH 3

H 3CN1) MnO 22) HCl
89% for 2 steps
H 3CO

CH 3O
CH 31) Dess Martin
2) TiCl4, NaBH 3CN

NOTBS
NHTBSO

97% for 2 steps
H 3CHOOHOTES
1) TBAF 100%OH

Cl(+)-DET, Ti(O-i-Pr)4,t-BuOOH
49%N
O

CH3HOOH
CH 3O

CH 3H 3C(+)-madindoline A
2.2

CH 3
OTBS

N+O
H 3C
:

O
H
CH 3O
CH 3(–)-madindoline B
1

Overall yield 7.8% in 19 steps

2) Second total synthesis4,6)

OH (+)-DIPT, Ti(O-i-Pr) 4
t-BuOOH

HO72%(>99% e.e.)

NHNH1) OHCHOCH 3OPiv

TBSO

AcOH, NaBH(OAc) 363%
2) TBSOTf 94%N

H 3C

HTBSO

1) EtMgBr,1,1'-(azodicarbonyl)dipiperidine

O2) NaClO 284% for 2 steps

H 3C

CO2HPivO
HOHOO
N H
CH 3

LDAO

TBSO
TMSCHN292%N

H 3C

O

CH 3Cl

H99%(>99% d.e.)

OO
N H
CH 3

TAS-F
56%

CO2MeTMS

TMS

NO

O

H 3C

CH 3(+)-madindoline B

CH 3

Overall yield 19% in 9 steps
HO

CO2Me
LDAO
ClO

CH 3CH 3 TMS

88%(>11 : 1 d.r.)

H 3C

HOO
N H
CH 3TBAT

CO2MeTMS52%O

CH 3O
N H
CH 3O

CH 3
H 3C(+)-madindoline A
Overall yield 16% in 9 steps3) Third total synthesis7)
HOCH 3HON H
HOTMSOCO2MeTMS

Bu

37% HCHO aq.,
Sc(OTf) 3,Sc(DS) 311%

NO

HOO
H
CH 3
CO2MeO
N H
CH 3O
O

TAS-F
77%
H 3CTMSCH 3HO+O

CH 31O

H 3C(+)-Madindoline A
ratio

ON H
CH 3(+)-Madindoline B:16. References
1. [647] M. Hayashi et al., J. Antibiot. 49, 1091-1095 (1996)
2. [688] S. Takamatsu et al., J. Antibiot. 50, 1069-1072 (1997)
3. [745] T. Sunazuka et al., J. Am. Chem. Soc. 122, 2122-2123 (2000)
4. [799] T. Hirose et al., Org. Lett. 4, 501-503 (2002)
5. [813] M. Hayashi et al., Proc. Natl. Acad. Sci. USA 99, 14728-14733 (2002)
6. [890] T. Hirose et al., Tetrhedron 61. 3396-3403 (2005)
7. [917] T. Hirose et al., Tetrhedron Lett. 47. 6761-6764 (2006)

CH 3HO