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Angew. Chem.-Int. Edit., Jun 19 2024, | https://doi.org/10.1002/anie.202405367
Hirocidins, Cytotoxic Metabolites from Streptomyces hiroshimensis, Induce Mitochondrion-mediated Apoptosis
Esther J. Han, [a] Myungeun Jeong, [a] Seoung Rak Lee,* [b] Erik J. Sorensen,* [a] and Mohammad R.Seyedsayamdost* [a,c]
[a] E. J. Han, M. Jeong, Prof. Dr. E. J. Sorensen, Prof. Dr. M. R. SeyedsayamdostDepartment of Chemistry, Princeton UniversityPrinceton, NJ 08544 (USA)
[b] Prof. Dr. S. R. LeeCollege of Pharmacy, Pusan National UniversityBusan 46241 (South Korea)
[c] Prof. Dr. M. R. SeyedsayamdostDepartment of Molecular Biology, Princeton UniversityPrinceton, NJ 08544 (USA)
Corresponding authors : Seoung Rak Lee, Erik J. Sorensen, Mohammad R.Seyedsayamdost
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.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-06-24)
- 국내(교신)+국외 연구진
- 의약학 > 약학
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