1. Hirocidins, Cytotoxic Metabolites from Streptomyces hiroshimensis, Induce Mitochondrion-Mediated Apoptosis.
- Author
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Han EJ, Jeong M, Lee SR, Sorensen EJ, and Seyedsayamdost MR
- Subjects
- Humans, Cell Proliferation drug effects, Cell Line, Tumor, Drug Screening Assays, Antitumor, Molecular Structure, Streptomyces metabolism, Streptomyces chemistry, Apoptosis drug effects, Mitochondria metabolism, Mitochondria drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism
- Abstract
Recent advances in whole genome sequencing have revealed an immense microbial potential for the production of therapeutic small molecules, even from well-known producers. To access this potential, we subjected prominent antimicrobial producers to alternative antiproliferative assays using persistent cancer cell lines. Described herein is our discovery of hirocidins, novel secondary metabolites from Streptomyces hiroshimensis with antiproliferative activities against colon and persistent breast cancer cells. Hirocidin A is an unusual nine-membered carbocyclic maleimide and hirocidins B and C are relatives with an unprecedented, bridged azamacrocyclic backbone. Mode of action studies show that hirocidins trigger mitochondrion-dependent apoptosis by inducing expression of the key apoptotic effector caspase-9. The discovery of new cytotoxins contributes to scaffold diversification in anticancer drug discovery and the reported modes of action and concise total synthetic route for variant A set the stage for unraveling specific targets and biochemical interactions of the hirocidins., (© 2024 Wiley-VCH GmbH.)
- Published
- 2024
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