104
D.C. Hill et al.
Pyripyropene A (the structure of which is shown in Fig. 8) inhibits ACAT
activity in microsomes with an IC5o of 58 nmol 1-1. It has no effect against
protein farnesyl transferase and diacylglycerol acyltransferase. The pyripyropenes were not cytotoxic in vitro and had low toxicity in vivo. Pyripyropene A showed significant activity in an in vivo model of cholesterol
adsorption in hamsters at a dose of 25 mgkg -1. ACAT inhibition by
N
H3CCO2~ICOC
H3
OCOCH 3
Ho.c 1
.o.c .-.J
H02C,,' " ~-0 / '-._
H
.....
O
~'~,~~NC H3~ OCH3
0
Fig. 8. Structures of the acyl CoA: cholesterol acyltransferase inhibitors pyripyropene A, 1,
and terpendole D, 2, the squalene synthase inhibitor squalestatin SI, 3 (Sect. 4.3.1), and a
diketopiperazine, 4, which inhibits plasminogen activator inhibitor-1 (Sect. 4.3.3)
D.C. Hill et al.
Pyripyropene A (the structure of which is shown in Fig. 8) inhibits ACAT
activity in microsomes with an IC5o of 58 nmol 1-1. It has no effect against
protein farnesyl transferase and diacylglycerol acyltransferase. The pyripyropenes were not cytotoxic in vitro and had low toxicity in vivo. Pyripyropene A showed significant activity in an in vivo model of cholesterol
adsorption in hamsters at a dose of 25 mgkg -1. ACAT inhibition by
N
H3CCO2~ICOC
H3
OCOCH 3
Ho.c 1
.o.c .-.J
H02C,,' " ~-0 / '-._
H
.....
O
~'~,~~NC H3~ OCH3
0
Fig. 8. Structures of the acyl CoA: cholesterol acyltransferase inhibitors pyripyropene A, 1,
and terpendole D, 2, the squalene synthase inhibitor squalestatin SI, 3 (Sect. 4.3.1), and a
diketopiperazine, 4, which inhibits plasminogen activator inhibitor-1 (Sect. 4.3.3)