Jiahui Wu, Yi Li, Kaixian Chen
Feb 1, 2013
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0
Influential Citations
18
Citations
Quality indicators
Journal
European journal of medicinal chemistry
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.