Discovery of 7-Methyl-10-Hydroxyhomocamptothecins with 1,2,3-Triazole Moiety as Potent Topoisomerase I Inhibitors

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• 作者：Xiguo Xu ; Yuelin Wu ; Wenfeng Liu ; Chuanquan Sheng ; Jianzhong Yao ; Guoqiang Dong ; Kun Fang ; Jin Li ; Zhiliang Yu ; Xiao Min ; Huojun Zhang ; Zhenyuan Miao and Wannian Zhang
• 刊名：Chemical Biology & Drug Design
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：88
• 期：3
• 页码：398-403
• 全文大小：744K
• ISSN：1747-0285

文摘

Homocamptothecin is emerging as an important topoisomerase I inhibitor originating in natural product camptothecin. We report the modifications and SAR of homocamptothecin on position C10 to develop potent topoisomerase I inhibitors for anticancer drug discovery. Based on click chemistry, twenty-one 1,2,3-triazole-substituted homocamptothecin derivatives were readily synthesized in two steps. For A549, cycloalkyl- and alkyl-substituted compounds 6j, 6l, and 6o revealed highly antiproliferative inhibitory activities with IC₅₀ value of 30, 30, and 50 nm, respectively. In addition, cyclopropyl 6j exhibited greater Topo I inhibitory activity than 20(S)-Camptothecin, which indicated suitability for further drug development.