文献类型：期刊文献

英文题名：Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents

作者：Wang, Shengzheng[1,2];Fang, Kun[1];Dong, Guoqiang[1];Chen, Shuqiang[1];Liu, Na[1];Miao, Zhenyuan[1];Yao, Jianzhong[1];Li, Jian[3];Zhang, Wannian[1];Sheng, Chunquan[1]

机构：[1]Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China;[2]Fourth Mil Med Univ, Sch Pharm, Xian 710032, Peoples R China;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

年份：2015

卷号：58

期号：16

起止页码：6678

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000360415800028)】；

基金：This work was supported in part by the National Natural Science Foundation of China (Grants 81373278 and 8122044), the 863 Hi-Tech Program of China (grant 2014AA020525), Science and Technology Commission of Shanghai (grant 11431920402 and 14YF1405400), and Shanghai "ShuGuang" Project (grant 14SG33).

语种：英文

摘要：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.