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


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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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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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).

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  • Chromenopyrroles
  • Phenotypic screening
  • Mitochondrial metabolism
  • Anticancer activity
  • Hepatoma cells
  • Immunotherapy