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

Hiroshi Tomoda, Hidetoshi Kumagai, Yuji Ogawa, Toshiaki Sunazuka, Hirokazu Hashizume, Hajime Nagashima, Satoshi Omura

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2161-2165
Number of pages5
JournalJournal of Organic Chemistry
Volume62
Issue number7
DOIs
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Organic Chemistry

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    Tomoda, H., Kumagai, H., Ogawa, Y., Sunazuka, T., Hashizume, H., Nagashima, H., & Omura, S. (1997). Synthesis of four chiral isomers of β-lactone DU-6622 and inhibition of HMG-CoA synthase by the specific (2R,3R)-isomer. Journal of Organic Chemistry, 62(7), 2161-2165. https://doi.org/10.1021/jo9621433