A Series of α-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIα Catalytic Activity

被引：188

作者：

Huang, He ^{[2
]}

Chen, Qin ^{[1
]}

Ku, Xin ^{[2
]}

Meng, Linghua ^{[1
]}

Lin, Liping ^{[1
]}

Wang, Xiang ^{[1
]}

Zhu, Caihua ^{[1
]}

Wang, Yi ^{[1
]}

Chen, Zhi ^{[2
]}

Li, Ming ^{[1
]}

Jiang, Hualiang ^{[2
]}

Chen, Kaixian ^{[2
]}

Ding, Jian ^{[1
]}

Liu, Hong ^{[2
]}

机构：

[1] Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 08期

基金：

中国国家自然科学基金;

关键词：

IRON CHELATORS; 2-ACETYLPYRIDINE THIOSEMICARBAZONES; ANTITUMOR-ACTIVITY; MULTIDRUG-RESISTANCE; DNA-CLEAVAGE; CELL-LINES; CYTOTOXICITY; POTENT; COMPLEXES; MECHANISM;

D O I：

10.1021/jm9014394

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase II alpha catalytic inhibitor. Its inhibition on topoisomerase II alpha was due to direct interaction with the ATPase domain of topoisomerase I la which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase II alpha.

引用

页码：3048 / 3064

页数：17

共 56 条

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