Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Simon J. Leiris, Omar Khdour, Zachary J. Segerman, Krystal S. Tsosie, Jean Chapuis, Sidney Hecht

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities. Also measured were the abilities of several of the analogues to inhibit respiration as judged by a shift to glycolysis, and to inhibit the growth of several mammalian cell lines. The nature of the pyrone ring was shown to be important to potency of inhibition, as was the length and nature of substituents in the side chain of the analogues.

Original languageEnglish (US)
Pages (from-to)3481-3493
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number10
DOIs
StatePublished - May 15 2010

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Keywords

  • Mitochondrial complex I
  • NADH oxidase
  • NADH-ubiquinone oxidoreductase
  • Verticipyrone analogues

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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