AI Article Synopsis
- Four chiral forms of the beta-lactone DU-6622 were synthesized to study their effect on HMG-CoA synthase inhibition.
- The (2R,3R)-beta-lactone isomer (+)-8a exhibited the strongest inhibitory activity with an IC(50) of 0.098 μM, indicating high potency.
- The other isomers showed significantly weaker inhibition, with IC(50) values ranging from 9.4 μM to 360 μM, highlighting that the specific stereochemistry of the (2R,3R) form is crucial for effective HMG-CoA synthase inhibition.
Article Abstract
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.
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