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ID: ALA3600310
Journal: J Med Chem
Title: Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents.
Authors: Wang S, Fang K, Dong G, Chen S, Liu N, Miao Z, Yao J, Li J, Zhang W, Sheng C.
Abstract: A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery.
CiteXplore: 26226379