Abstract
Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.
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Acknowledgements
We thank the laboratories of M. T. Hamann and R. T. Hill for providing Micromonospora sp. Strain M42, U. R. Abdelmohsen and U. Hentschel Humeida for providing Micromonospora sp. Strain RV43 and P. Jensen for providing Salinospora arenicola CNR107. C. Bak Nielsen is acknowledged for technical assistance. T.B.P. gratefully acknowledges support from the Lundbeck Foundation (fellow grant R105-A9308) and the Carlsberg Foundation (grant CF15-0431). T.T. gratefully acknowledges support from the Danish Council for Independent Research (DFF – 4181-00315).
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T.B.P. conceived and supervised the study, T.B.P., T.T. and N.L.V. designed the experiments. N.L.V., E.T.W., B.C. and U.B.K. performed the organic synthesis. K.M.J. conducted cytotoxicity experiments. N.L.V. and T.T. performed the bacterial fermentations and isolations, T.T. conducted the bioinformatic studies, U.B.K. and F.J. performed the computational studies. M.J., M.B. and T.V. helped with MS and NMR analyses. T.B.P., T.T. and N.L.V. wrote the manuscript with contributions from all authors.
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Villadsen, N., Jacobsen, K., Keiding, U. et al. Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products. Nature Chem 9, 264–272 (2017). https://doi.org/10.1038/nchem.2657
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DOI: https://doi.org/10.1038/nchem.2657
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