Synthesis of Four Chiral Isomers of beta-Lactone DU-6622 and Inhibition of HMG-CoA Synthase by the Specific (2R,3R)-Isomer.
Four chiral forms of the beta-lactone DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methoxycarbonyl)naphthalen-1-yl]pentanoic acid 1,3-lactone) were prepared to investigate their inhibitory activity against 3-hydroxy-3-methylglutarly-CoA (HMG-CoA) synthase. The (2R,3R)-beta-lactone isomer (+)-8a, having the same stereochemistry as that of the fungal beta-lactone 1233A, showed the most potent HMG-CoA synthase inhibitory activity (IC(50): 0.098 &mgr;M). The other three beta-lactone isomers, (2S,3R)- ((-)-8b), (2S,3S)- ((-)-8a), and (2R,3S)-isomers ((+)-8b), were weaker inhibitors with larger IC(50) values of 9.4, 31, and 360 &mgr;M, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the beta-lactone ring is responsible for HMG-CoA synthase inhibition.
Tomoda
Hiroshi
H
Research Center for Biological Function, The Kitasato Institute, and School of Pharmaceutical Sciences, Kitasato University, Minato-ku 108, Japan, Fuji Chemical Industries Co., Takaoka, Toyama 933, Japan, and Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo 134, Japan.
Kumagai
Hidetoshi
H
Ogawa
Yuji
Y
Sunazuka
Toshiaki
T
Hashizume
Hirokazu
H
Nagashima
Hajime
H
Omura
Satoshi
S