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

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.

Graphical abstractNew SIRT1 inhibitors with scaffold of benzofuran-3-yl(phenyl) methanone, as represented by (2,5 dihydroxyphenyl) (5-hydroxy- 1-benzofuran-3-yl)methanone (16), were designed and determined to bind in the C-pocket of SIRT1.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Benzofuran-3-yl(phenyl)methanone derivatives were identified as SIRT1 inhibitors. ► The inhibition pattern of the inhibitor was determined against the substrates. ► The inhibitor binds in the C-pocket of SIRT1. ► The binding mode was validated by structural modification and mutagenesis studies. ► The inhibitor up-regulates the acetylation of p53 on cellular level.