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Discovery of 7‐Methyl‐10‐Hydroxyhomocamptothecins with 1,2,3‐Triazole Moiety as Potent Topoisomerase I Inhibitors
Author(s) -
Xu Xiguo,
Wu Yuelin,
Liu Wenfeng,
Sheng Chuanquan,
Yao Jianzhong,
Dong Guoqiang,
Fang Kun,
Li Jin,
Yu Zhiliang,
Min Xiao,
Zhang Huojun,
Miao Zhenyuan,
Zhang Wannian
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12767
Subject(s) - camptothecin , moiety , natural product , chemistry , topoisomerase , triazole , click chemistry , stereochemistry , drug discovery , combinatorial chemistry , enzyme , biochemistry , organic chemistry
Homocamptothecin is emerging as an important topoisomerase I inhibitor originating in natural product camptothecin. We report the modifications and SAR of homocamptothecin on position C 10 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 A 549, cycloalkyl‐ and alkyl‐substituted compounds 6j , 6l , and 6o revealed highly antiproliferative inhibitory activities with IC 50 value of 30, 30, and 50 n m , respectively. In addition, cyclopropyl 6j exhibited greater T opo I inhibitory activity than 20( S )‐Camptothecin, which indicated suitability for further drug development.