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

Nature Chemical Biology volume 4, pages 418–424 (2008)Cite this article

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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Figure 1
Figure 2
Figure 3: Effect of analog 3 on S. cerevisiae growth.
Figure 4: Effect of leucascandrolide A analog 3 and neopeltolide on S. cerevisiae on agar plates.
Figure 5: Inhibition of ATP production in A549 cells in response to treatment with neopeltolide and leucascandrolide analog 3, in the presence or absence of 2-DG.
Figure 6: Effect of leucascandrolide analog 3 and neopeltolide on cellular respiration, NADH consumption and activity of cytochrome bc1 complex.

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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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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, 60637, Illinois, USA

    Olesya A Ulanovskaya, Jelena Janjic, Masato Suzuki & Sergey A Kozmin

  2. Department of Pediatrics, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois, 60611, USA

    Simran S Sabharwal & Paul T Schumacker

  3. Ludwig Center for Metastasis Research, University of Chicago, Chicago, 924 East 57th Street, 60637, Illinois, USA

    Stephen J Kron

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  1. Olesya A Ulanovskaya
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Contributions

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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Correspondence to Sergey A Kozmin.

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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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