Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole

doi:10.1016/j.bmcl.2014.05.028

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	Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
	Wu, Jiahui 1; Li, Jianneng 3; Xu, Ming-Hua2 ; Liu, Dongxiang1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2014-07-15
卷号	24 期号:14 页码:3050-3056
关键词	SIRT1 3-(Furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives Inhibitor Structure-activity relationship Protein-ligand interaction Deacetylation
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2014.05.028
文献子类	Article
英文摘要	SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1. (C) 2014 Elsevier Ltd. All rights reserved.
资助项目	Chinese Academy of Sciences[00000000] ; National Science Fund for Creative Research Groups[21021063] ; Science and Technology Commission of Shanghai Municipality[08JC1422100]
WOS关键词	CRYSTAL-STRUCTURE ; EADOCK DSS ; MECHANISM ; DEACETYLASE ; NICOTINAMIDE ; DISCOVERY ; SIRTUINS ; DISEASE ; NAD(+)
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000338809400012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276987]
专题	药理学第三研究室
通讯作者	Liu, Dongxiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 3.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式 GB/T 7714	Wu, Jiahui,Li, Jianneng,Xu, Ming-Hua,et al. Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2014,24(14):3050-3056.
APA	Wu, Jiahui,Li, Jianneng,Xu, Ming-Hua,&Liu, Dongxiang.(2014).Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,24(14),3050-3056.
MLA	Wu, Jiahui,et al."Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 24.14(2014):3050-3056.