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

Add time:07/18/2019    Source:sciencedirect.com

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.

We also recommend Trading Suppliers and Manufacturers of (3-Chlorophenyl)(phenyl)methanone (cas 1016-78-0). Pls Click Website Link as below: cas 1016-78-0 suppliers

Prev:An efficient method for the synthesis of 1-chlorophenazines based on the selective cathodic reduction of 3,3,6,6-tetrachloro-1,2-cyclohexanedione
Next:Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents)