title: Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: binding mode, inhibitory mechanism and biological action.
abstract: 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.
authors: Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors: Jiahui
authors: J
authors: Wu
authors: Yi
authors: Y
authors: Li
authors: Kaixian
authors: K
authors: Chen
authors: Hualiang
authors: H
authors: Jiang
authors: Ming-Hua
authors: MH
authors: Xu
authors: Dongxiang
authors: D
authors: Liu
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C582775:(2,5-dihydroxyphenyl)(5-hydroxybenzofuran-3-yl)methanone; D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006873:Hydroquinones; C447939:SIRT1 protein, human; D056564:Sirtuin 1