Absolute stereochemistry of fungal beauveriolide III and ACAT inhibitory activity of four stereoisomers

Taichi Ohshiro, Ichiji Namatame, Kenichiro Nagai, Takafumi Sekiguchi, Takayuki Doi, Takashi Takahashi, Kazuaki Akasaka, Lawrence L. Rudel, Hiroshi Tomoda, Satoshi Omura

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

(Chemical Equation Presented) Fungal beauveriolide III (BeauIII, 1b), a cyclodepsipeptide inhibiting acyl-CoA:cholesterol acyltransferase (ACAT) and showing antiatherogenic activity in mouse models, consists of L-Phe, L-Ala, D-allo-Ile, and 3-hydroxy-4-methyloctanoic acid (HMA) moieties, but the stereochemistry of the HMA part has not until now been fully defined. To determine it, four HMA stereoisomers were synthesized and labeled with (S)-(+)-2-(anthracene-2,3-dicarboximido)-1-propyl trifluoromethane sulfonate (AP-OTf), a chiral fluorescent reagent. The derivatives were separated by HPLC and compared with the natural HMA derivative, which was thereby identified as (3S,4S)HMA in BeauIII. Furthermore, the four beauveriolide III isomers ((3S,4S)BeauIII (23a), (3R,4R)BeauIII (23b), (3R,4S)BeauIII (23c), and (3S,4R)BeauIII (23d)) were synthesized, and it was shown that all the spectral data for 23a were identical with those for natural 1b. Isomers 23a and 23d showed potent inhibitory activity of lipid droplet accumulation in macrophages, while the other two isomers caused weak inhibition. Thus, the 3S configuration of BeauIII is important for this activity. Furthermore, 23a and 23d showed rather specific inhibition against the ACAT1 isozyme.

Original languageEnglish
Pages (from-to)7643-7649
Number of pages7
JournalJournal of Organic Chemistry
Volume71
Issue number20
DOIs
Publication statusPublished - 2006 Sep 29
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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