Synthesis of four chiral isomers of beta-lactone DU-6622 and inhibition of HMG-CoA synthase by the specific (2R,3R)-isomer

被引:11
作者
Tomoda, H
Kumagai, H
Ogawa, Y
Sunazuka, T
Hashizume, H
Nagashima, H
Omura, S
机构
[1] KITASATO INST,BIOL FUNCT RES CTR,MINATO KU,TOKYO 108,JAPAN
[2] KITASATO UNIV,SCH PHARMACEUT SCI,MINATO KU,TOKYO 108,JAPAN
[3] FUJI CHEM IND CO LTD,TAKAOKA,TOYAMA 933,JAPAN
[4] DAIICHI PHARMACEUT CO LTD,RES INST,EDOGAWA KU,TOKYO 134,JAPAN
关键词
COENZYME-A SYNTHASE; SIDE-CHAIN MIMICKING; 3-HYDROXY-3-METHYLGLUTARYL COENZYME; CHOLESTEROL-BIOSYNTHESIS; BIOLOGICAL-ACTIVITY; HYDROXYMETHYLGLUTARYL-COENZYME; ANTIBIOTIC; 1233A; 2-OXETANONES; F-244; EBELACTONE;
D O I
10.1021/jo9621433
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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(IC50: 0.098 mu M). The other three beta-lactone isomers, (2S,3R)- ((-)-8b), (2S,3S)- ((-)-8a), and (2R,3S)-isomers ((+)-8b), were weaker inhibitors with larger IC50 values of 9.4, 31, and 360 mu M, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the beta-lactone ring is responsible for HMG-CoA synthase inhibition.
引用
收藏
页码:2161 / 2165
页数:5
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