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Synthesis of marmycin A and investigation into its cellular activity

Nature Chemistry volume 7, pages 744–751 (2015)Cite this article

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Abstract

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels–Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel–Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications.

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Figure 1: Anthraquinone-containing natural products.
Figure 2: Chemical synthesis of the marmycins.
Figure 3: Marmycin A kills human cancer cells independently of genome targeting.
Figure 4: Marmycin A accumulates in the lysosomes and triggers programmed cell death.
Figure 5: Antiproliferative mechanisms of anthraquinone-containing drugs.

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Acknowledgements

The authors thank the CNRS for funding, and the Imagif Cell Biology Unit, J.-F. Gallard and F. Blanchard for assistance with cell imaging, NMR spectroscopy and X-ray crystallography, respectively. R.R. thanks J.A. Yeoman, S. Müller, J.E. Moses, S.L. Buchwald, L. Johannes, M. Mehrpour and members of R.R.’s laboratory for discussions and proofreading of this manuscript. Research in R.R.’s laboratory is supported by the European Research Council (grant no. 647973), the Fondation pour la Recherche Médicale (grant no. AJE20141031486), the Emergence Ville de Paris Program and the Ligue Nationale Contre le Cancer.

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Author notes

  1. Filipe Gomes and Trang Thi Mai: These authors contributed equally to this work

Authors and Affiliations

  1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, 1 Avenue de la Terrasse, Gif sur-Yvette, 91198, France

    Tatiana Cañeque, Filipe Gomes, Trang Thi Mai, Giovanni Maestri, Max Malacria & Raphaël Rodriguez

  2. Department of Chemistry, Università degli Studi di Parma, Parco Area delle Scienze 17/a, Parma, 43124, Italy

    Giovanni Maestri

  3. Institut Parisien de Chimie Moléculaire, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8232, Paris CEDEX 05, 75252, France

    Max Malacria

  4. Institut Curie Research Center, Organic Synthesis and Cell Biology Group, 26 rue d'Ulm, Paris Cedex 05, 75248, France

    Raphaël Rodriguez

  5. CNRS UMR 3666, Paris, 75005, France

    Raphaël Rodriguez

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Contributions

R.R., with contributions from T.C., G.M. and M.M., conceived and designed the experiments. T.C., with assistance from F.G., synthesized the marmycins and artesumycin. T.T.M. with contribution from T.C. performed proliferation assays, fluorescence-activated cell sorting, western blotting and cellular imaging. R.R., G.M. and M.M. supervised the research. All the authors analysed the data. R.R. wrote the manuscript. All the authors commented on the manuscript. T.T.M. and F.G. contributed equally to this work.

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Correspondence to Raphaël Rodriguez.

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The authors declare no competing financial interests.

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Cañeque, T., Gomes, F., Mai, T. et al. Synthesis of marmycin A and investigation into its cellular activity. Nature Chem 7, 744–751 (2015). https://doi.org/10.1038/nchem.2302

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