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Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism

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Abstract

Chromenopyrrole derivatives with multiple stereocenters and variable ring fusion pattern are found in many natural products and biologically appealing molecules. By employing a build/couple/pair strategy, we have recently reported on the discovery of a serendipitous cascade to access a diverse collection of chromenopyrroles. This protocol features a one-pot cascade that includes the generation of azomethine ylide and intramolecular [3 + 2]-cycloaddition. Phenotypic screening of the developed pilot library enabled the identification of chemical probes that efficiently suppress mitochondrial membrane potential, elevate reactive oxygen species content, and deplete ATP content in a hepatoma cell line (Hepa1-6), without affecting the proliferation of T- or B-cells. This selective targeting represents a new approach for the treatment of cancer.

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Acknowledgements

This work was supported by grants from Terry Fox Foundation (grant number 120403), the Research Funding Department at the University of Sharjah (grant number 1801110125-P), and a research grant (BBRI-AS0215) to A.F.M. and I.A.A. from the American University of Sharjah.

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Authors and Affiliations

  1. Lübeck Institute of Experimental Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Paul Schilf & Saleh Ibrahim

  2. Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE

    Vunnam Srinivasulu, Hany A. Omar, Raafat ElAwady & Taleb H. Al-Tel

  3. Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Via Belmeloro, 6, 40126, Bologna, Italy

    Maria L. Bolognesi

  4. Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, P.O. Box 26666, Sharjah, UAE

    Amin F. Majdalawieh & Imad A. Abu-Yousef

  5. College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, UAE

    Hany A. Omar, Raafat ElAwady & Taleb H. Al-Tel

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  1. Paul Schilf
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Correspondence to Taleb H. Al-Tel.

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Schilf, P., Srinivasulu, V., Bolognesi, M.L. et al. Design and synthesis of nature-inspired chromenopyrroles as potential modulators of mitochondrial metabolism. Med Chem Res 30, 635–646 (2021). https://doi.org/10.1007/s00044-020-02669-3

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