文献类型：期刊文献

英文题名：Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma

作者：Cui, Guangwei[1,2];Fan, Yuhang[2,3];Yang, Yue[1,2];Ma, Yiwen[1,2];Deng, Haiyang[1,2];Wang, Pan[1,2];Zhu, Yuxin[1,2];Li, Jian[2,3];Wei, Jinlian[2,3];Zhang, Yongqiang[1,2]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[3]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2024

卷号：68

期号：1

起止页码：247

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001379384400001)】；

基金：Financial support from the program of the National Natural Science Foundation of China (21602060, 21871086, and 22171080, Y.-Q.Z.) and Natural Science Foundation of Shanghai Municipality (23ZR1417200, Y.-Q.Z.) is gratefully acknowledged.

语种：英文

摘要：The search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel N-trifluoromethylated noscapines has been disclosed. Among them, 9 '-bromo-N-trifluoromethyl noscapine 15c displayed superior in vitro anti-GBM potency. Unexpectedly, in contrast with the general N-trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where N-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, 15c showed excellent BBB permeability and good in vivo anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that 15c exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.