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A Series of Alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIalpha Catalytic Activity

A Series of Alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase IIalpha Catalytic Activity

He Huang, Qin Chen, Xin Ku, Linghua Meng, Liping Lin, Xiang Wang, Caihua Zhu, Yi Wang, Zhi Chen, Ming Li, Hualiang Jiang, Kaixian Chen, Jian Ding, Hong Liu

J Med Chem. 2010 Apr 22;53(8):3048-64.

PMID: 20353152

Abstract:

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 IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha 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 IIalpha.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415761	Topoisomerase IIα Inhibitor, TSC24			Price

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