Isochromophilone

1. Discovery, producing organism and structures1-5)Isochromophilones I and II were isolated from the culture broth of Penicillium multicolor FO23381,3,4). They were found to be novel gp120-CD4 binding inhibitors. Isochromophilones III–VI
were isolated from the culture broth of Penicillium sp. FO-3216 and recognized as inhibitors ofacyl-CoA: cholesterol acyltransferase (ACAT)2). Isochromophilones VII and VIII were isolated
from the culture broth of Penicillium sp. FO-41645) and found to be inhibitors of both ACAT anddiacylglycerol acyltransferse (DGAT). The structures of isochromophilones were elucidated by
NMR analysis. Isochromophilones, members of the azaphilone family, have an oxoisochromanering. Among this group, isochromophilone I is a complex of two isomers (a and b) which areeasily converted from one isoform to another.

Penicillium multicolor FO-2338
Bar: 5 µmClCl

CH3 CH3O
H3C

CH3a3OOHO

CH3CH3OHO

Isochromophilone IICl

CH3 CH3CH3CH3 CH3CH3O

HOOCH3bIsochromophilone IClO
H3CCH3HOH3CCH3O
H3CO

HOHO

Isochromophilone IIIClOHOIsochromophilone VH3C
H3COOOO

Isochromophilone VII

N

Isochromophilone VI
CH3 CH3CH3O
H3CHOOHOClCH3OH

CH3 CH3CH3O

CH3 CH3Cl

Isochromophilone IVO
H3C
H3COO

CH3Cl
CH3HOHOCH3 CH3O
H3C

CH3 CH3O
H3C

3O

HO

Penicillium sp. FO-4164
Bar: 5 µm

Penicillium sp. FO-3216
Bar: 5 µm

OO

HO

CH3Isochromophilone VIII

Br

CH3 CH3O

CH3O
H3C
HO

CH3H3COO

HO

CH3 CH3HO

Isochromophilone VIIOH
CH3O

Isochromophilone VIII

2. Physical data (Isochromophilone I)Yellow powder. C23H25O5Cl; mol wt 416.14. Sol. in acetone, CHCl3, EtOH, MeOH, EtOAc. Insol. in hexane, H2O.
3. Biological activity1-3,5)
1) Inhibition of gp120-CD4 binding1,3)
Compound

IC50 (µM)*

Isochromophilone I
Isochromophilone II

6.6
3.9

* Binding activity between recombinant soluble CD4 and recombinant 		
gp120 was determined by ELISA.

2) Inhibition of HIV replication1)					CompoundViral core protein p24 synthesized (ng/ml)
Day 2
Day 3Day 4None
Isochromophilone II (10 µg/ml)

0097.30129.613.53) Inhibition of DGAT and ACAT activities2,5)IC50 (µM)
CompoundIsochromophiloneIII		IVV		VIVIIVIII

DGAT

ACATNT
63.5
NTNT
20.0
127

110
50.0
50.0
120
24.5
47.0

NT; not tested
DGAT and ACAT activities were analyzed by enzyme
assays using rat liver microsomes as an enzyme source.

4) Inhibition of CETP activities by azaphilones6)
Certain members of the azaphilone family were found to inhibit CETP activity. Chaetoviridin B
showed the most potent CETP inhibition with an IC50 value of < 6.2 µM, followed by sclerotiorin (IC50; 19.4 µM) and deacetylsclerotiorin (IC50; 19.4 µM). From the SAR, the common substructure shown below is essential for eliciting CETP inhibitory activity. Azaphilones are thought
to react with primary amines in CETP to form adducts.
OO
54326789O110OO

Common substructure of azaphilones essential for eliciting CETP inhibition
Sclerotiorin
OOOO
O
NH2–X (Protein)

OOO

OH N HXOH N HXOOOH

HOOH NXONHXNOA possible reaction mechanism for formation of sclerotiorin adducts

4. References
1. [529] S. Ōmura et al., J. Antibiot. 46, 1908-1911 (1993)
2. [578] N. Arai et al., J. Antibiot. 48, 696-702 (1995)
3. [579] K. Matsuzaki et al., J. Antibiot. 48, 703-707 (1995)
4. [580] K. Matsuzaki et al., J. Antibiot. 48, 708-713 (1995)
5. [607] D. J. Yang et al., J. Antibiot. 49, 223-229 (1996)
6. [714] H. Tomoda et al., J. Antibiot. 52, 160-170 (1999)
7. [705] K. Matsuzaki et al., J. Antibiot. 51, 1004-1011 (1998)

X