Abstract
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.
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Acknowledgements
This work was supported by the US National Cancer Institute (R01 CA93457 to S.A.K.) and the US National Institutes of Health (R01 GM60443 to S.J.K.). S.A.K. thanks the Alfred P. Sloan Foundation, the Dreyfus Foundation, Amgen and GlaxoSmithKline for additional financial support. S.J.K. was a Leukemia & Lymphoma Society Scholar. J.J. acknowledges the support of Burroughs Wellcome Fund Interfaces 1001774.
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O.A.U., J.J., P.T.S., S.J.K. and S.A.K. planned the project. S.S.S. contributed to experiments depicted in Figure 6d. M.S. contributed to the synthesis shown in Scheme 2. O.A.U. and J.J. performed all other experiments. O.A.U., S.J.K. and S.A.K. wrote the paper. All authors discussed the results and commented on the manuscript.
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Ulanovskaya, O., Janjic, J., Suzuki, M. et al. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nat Chem Biol 4, 418–424 (2008). https://doi.org/10.1038/nchembio.94
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DOI: https://doi.org/10.1038/nchembio.94
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