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

drzmm 添加于 2010-7-7 11:24 | 1619 次阅读 | 0 个评论

作者
Huang H, Chen Q, Ku X, Meng L, Lin L, Wang X, Zhu C, Wang Y, Chen Z, Li M, Jiang H, Chen K, Ding J, Liu H
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 IIα catalytic inhibitor. Its inhibition on topoisomerase IIα was due to direct interaction with the ATPase domain of topoisomerase IIα 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 IIα.
详细资料
- 文献种类:期刊
- 期刊名称: Journal of Medicinal Chemistry
- 期刊缩写: J. Med. Chem.
- 期卷页: 2010年第53卷第8期 3048-3064页
- ISBN: 0022-2623
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