Design, synthesis, and biological evaluation of beauveriolide analogues bearing photoreactive amino acids

Yuichi Masuda, Kazumasa Aoyama, Masahito Yoshida, Keisuke Kobayashi, Taichi Ohshiro, Hiroshi Tomoda, Takayuki Doi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Beauveriolides I and III, which are naturally occurring cyclodepsipeptides, have been reported to bind to sterol O-acyltransferase (SOAT), inhibiting its ability to synthesize cholesteryl esters. To facilitate an analysis of the binding site(s) of these compounds, we designed beauveriolide analogues 1a-d wherein the Leu or D-allo-Ile residue was replaced by photoreactive amino acids possessing methyldiazirine or trifluoromethyldiazirine in the side chains. The methyldiazirine moiety was installed by reaction of methyl ketones with liquid ammonia to provide imine intermediates, followed by treatment with hydroxylamine-O-sulfonic acid to provide the diaziridines. Subsequent oxidation gave methyldiazirines. In contrast, trifluoromethyldiazirine derivatives were prepared from trifluoromethyl ketones via the oxime intermediates, which were transformed into diaziridines. Subsequent oxidation afforded trifluoromethyldiazirines. The synthesized photoreactive amino acids 3a-d were coupled with 3-hydroxy-4-methyloctanoic acid 4 and dipeptide 5, followed by macrolactamization to provide beauveriolide analogues 1a-d. The SOAT inhibitory activities of 1a-d were found to be as potent as those of beauveriolides I and III. Moreover, 1a-d inhibited SOAT1 selectively rather than SOAT2, which was also consistent with the behavior of beauveriolides I and III.

Original languageEnglish
Pages (from-to)754-765
Number of pages12
JournalChemical and Pharmaceutical Bulletin
Volume64
Issue number7
DOIs
Publication statusPublished - 2016 Jan 1

Keywords

  • Beauveriolide
  • Diazirine
  • Photoaffinity labeling
  • Sterol O-acyltransferase

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery

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