Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action

doi:10.1016/j.ejmech.2012.12.026

	Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action
	Wu, Jiahui 2; Li, Yi 1; Chen, Kaixian3 ; Jiang, Hualiang3 ; Xu, Ming-Hua1 ; Liu, Dongxiang2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2013-02
卷号	60 页码:441-450
关键词	Benzofuran-3-yl(phenyl)methanones Binding mode Deacetylation Inhibitor SIRT1
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2012.12.026
文献子类	Article
英文摘要	SIRT1 is a NAD(+)-dependent deacetylase. Here we described new SIRT1 inhibitors with the scaffold of benzofuran-3-yl(phenyl)methanone. The inhibitors were predicted to bind in C-pocket of SIRT1, forming hydrophobic interactions with Phe273, Phe312 and Ile347. Introducing hydroxyl to meta position of phenyl may form H-bond with Asn346. Indeed, (2,5-dihydroxyphenyl)(5-hydroxy-1-benzofuran-3-yl) methanone (16), an analogue with hydroxyls at ortho and meta positions, showed greater inhibition. The binding mode was validated by structural modifications and kinetic studies. Since C-pocket is the site where the nicotinamide moiety of NAD(+) binds and the hydrolysis takes place, binding of 16 in C-pocket would block the transformation of NAD(+) to productive conformation and hence inhibit the deacetylase activity. Consistently, 16 inhibited SIRT1 through up-regulating p53 acetylation on cellular level. (C) 2012 Elsevier Masson SAS. All rights reserved.
资助项目	CAS[00000000] ; National Science Fund for Creative Research Groups[21021063] ; Science and Technology Commission of Shanghai Municipality[08JC1422100]
WOS关键词	SMALL-MOLECULE ACTIVATORS ; CELL-SURVIVAL ; TRANSCRIPTION FACTORS ; P53 ACETYLATION ; DEACETYLASE ; NICOTINAMIDE ; RESTRICTION ; REGULATOR ; DISCOVERY ; SIRTINOL
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000316242700044
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277738]
专题	药物化学研究室药理学第三研究室
通讯作者	Xu, Ming-Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol 3, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wu, Jiahui,Li, Yi,Chen, Kaixian,et al. Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,60:441-450.
APA	Wu, Jiahui,Li, Yi,Chen, Kaixian,Jiang, Hualiang,Xu, Ming-Hua,&Liu, Dongxiang.(2013).Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,60,441-450.
MLA	Wu, Jiahui,et al."Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 60(2013):441-450.