TY - JOUR
T1 - Synthesis of four chiral isomers of β-lactone DU-6622 and inhibition of HMG-CoA synthase by the specific (2R,3R)-isomer
AU - Tomoda, Hiroshi
AU - Kumagai, Hidetoshi
AU - Ogawa, Yuji
AU - Sunazuka, Toshiaki
AU - Hashizume, Hirokazu
AU - Nagashima, Hajime
AU - Omura, Satoshi
PY - 1997/1/1
Y1 - 1997/1/1
N2 - Four chiral forms of the β-lactone DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methoxycarbonyl)naphthalen-1-yl]pen tanoic acid 1,3-lactone) were prepared to investigate their inhibitory activity against 3-hydroxy-3-methylglutarly-CoA (HMC-CoA) synthase. The (2R,3R)-β-lactone isomer (+)8a, having the same stereochemistry as that of the fungal β-lactone 1233A, showed the most potent HMG-CoA synthase inhibitory activity (IC50: 0.098 μM). The other three β-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 μM, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the β-lactone ring is responsible for HMG-CoA synthase inhibition.
AB - Four chiral forms of the β-lactone DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methoxycarbonyl)naphthalen-1-yl]pen tanoic acid 1,3-lactone) were prepared to investigate their inhibitory activity against 3-hydroxy-3-methylglutarly-CoA (HMC-CoA) synthase. The (2R,3R)-β-lactone isomer (+)8a, having the same stereochemistry as that of the fungal β-lactone 1233A, showed the most potent HMG-CoA synthase inhibitory activity (IC50: 0.098 μM). The other three β-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 μM, respectively. Thus, it was concluded that the (2R,3R) stereochemistry of the β-lactone ring is responsible for HMG-CoA synthase inhibition.
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U2 - 10.1021/jo9621433
DO - 10.1021/jo9621433
M3 - Article
C2 - 11671524
AN - SCOPUS:0030921945
SN - 0022-3263
VL - 62
SP - 2161
EP - 2165
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 7
ER -