A Series of alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase II alpha Catalytic Activity

doi:10.1021/jm9014394

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	A Series of alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase II alpha Catalytic Activity
	Huang, He 2; Chen, Qin 1; Ku, Xin 2; Meng, Linghua1 ; Lin, Liping 1; Wang, Xiang 1; Zhu, Caihua 1; Wang, Yi 1; Chen, Zhi 2; Li, Ming1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2010-04-22
卷号	53 期号:8 页码:3048-3064
ISSN号	0022-2623
DOI	10.1021/jm9014394
文献子类	Article
英文摘要	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.
资助项目	National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[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]
WOS关键词	MEDIATED DNA CLEAVAGE ; HERPES-SIMPLEX VIRUS ; BREAST-CANCER CELLS ; GYRASE-B PROTEIN ; IRON CHELATORS ; ANTITUMOR-ACTIVITY ; 2-ACETYLPYRIDINE THIOSEMICARBAZONES ; ANTIPROLIFERATIVE AGENTS ; ANTILEUKEMIC ACTIVITY ; MULTIDRUG-RESISTANCE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000276562400005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278915]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心药物化学研究室
通讯作者	Meng, Linghua
作者单位	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
推荐引用方式 GB/T 7714	Huang, He,Chen, Qin,Ku, Xin,et al. A Series of alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase II alpha Catalytic Activity[J]. JOURNAL OF MEDICINAL CHEMISTRY,2010,53(8):3048-3064.
APA	Huang, He.,Chen, Qin.,Ku, Xin.,Meng, Linghua.,Lin, Liping.,...&Liu, Hong.(2010).A Series of alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase II alpha Catalytic Activity.JOURNAL OF MEDICINAL CHEMISTRY,53(8),3048-3064.
MLA	Huang, He,et al."A Series of alpha-Heterocyclic Carboxaldehyde Thiosemicarbazones Inhibit Topoisomerase II alpha Catalytic Activity".JOURNAL OF MEDICINAL CHEMISTRY 53.8(2010):3048-3064.