期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 8, 页码 3048-3064出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm9014394
关键词
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资金
- National Natural Science Foundation of China [20721003, 20872153]
- 863 Hi-Tech Program of China [2006AA020602]
- State Key Program of Basic Research of China [2009CB918502]
- Science and Technology Commission of Shanghai Municipality [07dz05906]
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.
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