Purpactin

1. Discovery, producing organism and structure1,2,6)
Purpactins were isolated from the culture broth of Penicillium purpurogenum (current name:Talaromyces purpurogenus6)) FO-608 and found to be inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) from an assay using rat liver microsomes an enzyme source.
H3C
H3CO O

H3CO

H3COCOO

CH3

HOPurpactin A
H3C
H3C

H3COO O

H3COCO

Penicillium purpurogenum FO-608(Talaromyces purpurogenus FO-608)
Bar: 5 µm

CH3O
RPurpactin B R = CH2OH
C R = CHO

2. Physical data (Purpactin A)1)
Colorless powder. C23H26O7; mol wt 414.17. Sol. in MeOH, CHCl3. Insol. in hexane, H2O.
3. Biological activity1,7)
ACAT play an important role in three events that contribute to the atherosclerotic process; absorption of dietary cholesterol from the intestines, lipoprotein synthesis in the liver and accumulation of cholesteryl esters as oil droplets in macrophages and smooth muscle cells of developing
arterial lesions. Therefore, ACAT inhibitors are expected to retard progression of atherosclerosis.
ACAT inhibitory activity was tested in an enzyme assay using rat liver microsomes and in a cellassay using J774 macrophages. Cytotoxicity (CD50) was also determined by the cell assay. Purpactins are as the first microbial ACAT inhibitors discovered.
CompoundPurpactin A
Purpactin B
Purpactin C

Rat liver microsomes

J774 macrophages

IC50 (µM)

IC50 (µM) CD50 (µM)

121
126
126

1.2NT
NT

9.7
NTNT

Purpactin A inhibited ACAT1 (IC50= 2.5 μM) and ACAT2 (IC50= 1.5 μM,) to similar extent.7)
4. Biosynthesis2,3)
Purpactin B is the first isogrisan compound derived from a single octaketide chain. It is nonenzymatically converted to purpactin A in accordance with the following scheme2).

13

CH3–13COONa X 8■●Decarboxylation
CO2O
●

■●■■
●

●

■
●

■

●

■
●

■

●

●

HOSCH3(CH2)2OH

H2NO O●● ■■ ●■■● ■●● O ● ■
■

COOH

■

■

OH

OH
HOO

OH

●

●●

■
●

■

■
●

Oxidative cleavage [O]

■●■

■
●

■X■

■

OO■

●

■X = O or H2●

OCH3 O O
CH3COO■●■●●■ ●●■● ■■● ■■HOOOHHOO

OH●●

●

●

●

●

■
●

■■
●

■
●OH■■■■●

●■■●

■

OH

■●OH■■OH■■●

Purpactin B

O ● ■●OCH3O■■CH3COOOH■●●●■■
●

●

OO ■
HO■
● ■

● ■

● ■

Purpactin A

5. Chemical modification4)
Acylated derivatives were prepared from deacetylated purpactin (penicillide)5) and their ACAT
H3C
inhibitory activity was tested.
H3C
R1O

H3CO O
1'OO
R2O 11			Derivative1 a)2 b)3		4		5		6		7		8		9		10		11		12		13		

CH3R1R2Rat (liver) microsomes(C-1')(C-11)

IC50 (µM)

IC50 (µM)

CD50 (µM)

CD50/IC50

CH3CO
H
CH3CO
H
CH3(CH2)14CO
CH3(CH2)2CO
CH3CO
CH3CO
H
CH3(CH2)14COH
CH3(CH2)2CO
CH3CO

H		
H		
THP c)c)
THP
H		
H		
CH3(CH2)14CO
CH3(CH2)2COCH3(CH2)14CO
CH3(CH2)14CO
CH3(CH2)2COCH3(CH2)2CO
CH3		120>269
84
182>164
60>15381>164>11860
88
224

1.2>26.9
5.0
28.5>16.4
1.4>15.3
2.5>16.4>11.8>30.1>19.6
11.7

9.7>26.9>25.1>28.5>16.4
9.3>15.3>20.7>16.4>11.8>11.6>19.6
9.3

8.1
–>8.4
>1.0–
6.6–>8.3––<2.6<1.00.8a) Purpactin A b) Penicillide c) Tetrahydropyranyl

J774 macrophages

6. References
1. [457] H. Tomoda et al., J. Antibiot. 44, 136-143 (1991)
2. [458] H. Nishida et al., J. Antibiot. 44, 144-151 (1991)
3. [477] H. Nishida et al., J. Org. Chem. 57, 1271-1274 (1992)
4. [459] H. Nishida et al., J. Antibiot. 44, 152-159 (1991)
5.		
T. Sassa et al., Tetrahedron Lett. 45, 3941-3942 (1974)
6. 		
R. A. Samson et al. Stud. Mycol. 70, 159-183 (2011)
7. [955] T. Ohshiro et al., J. Antibiot. 60, 43-51 (2007)