Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide

Olesya A. Ulanovskaya, Jelena Janjic, Masato Suzuki, Simran S. Sabharwal, Paul T. Schumacker, Stephen J. Kron, Sergey A. Kozmin

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


Leucascandrolide A and neopeltolide are structurally homologous marine natural products that elicit potent antiproliferative profiles in mammalian cells and yeast. The scarcity of naturally available material has been a significant barrier to their biochemical and pharmacological evaluation. We developed practical synthetic access to this class of natural products that enabled the determination of their mechanism of action. We demonstrated effective cellular growth inhibition in yeast, which was substantially enhanced by substituting glucose with galactose or glycerol. These results, along with genetic analysis of determinants of drug sensitivity, suggested that leucascandrolide A and neopeltolide may inhibit mitochondrial ATP synthesis. Evaluation of the activity of the four mitochondrial electron transport chain complexes in yeast and mammalian cells revealed cytochrome bc1 complex as the principal cellular target. This result provided the molecular basis for the potent antiproliferative activity of this class of marine macrolides, thus identifying them as new biochemical tools for investigation of eukaryotic energy metabolism.

Original languageEnglish (US)
Pages (from-to)418-424
Number of pages7
JournalNature Chemical Biology
Issue number7
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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