191729-33-6Relevant academic research and scientific papers
Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: Binding mode, inhibitory mechanism and biological action
Wu, Jiahui,Li, Yi,Chen, Kaixian,Jiang, Hualiang,Xu, Ming-Hua,Liu, Dongxiang
, p. 441 - 450 (2013/03/29)
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.
