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.

SIRT1是NAD ⁺依赖性脱乙酰基酶。在这里我们描述了新的SIRT1抑制剂与苯并呋喃-3-基（苯基）甲酮的支架。预计这些抑制剂会结合在SIRT1的C型口袋中，与Phe273，Phe312和Ile347形成疏水相互作用。将羟基引入苯基的间位可以与Asn346形成H键。实际上，（2，5-二羟基苯基）（5-羟基-1-苯并呋喃-3-基）甲酮（16），在邻位和间位具有羟基的类似物，表现出更大的抑制作用。通过结构修饰和动力学研究验证了结合模式。由于C口袋是NAD ⁺烟酰胺部分结合并发生水解的位点，因此C口袋中16的结合会阻止NAD的转化⁺至生产构象，因此抑制了脱乙酰基酶的活性。一致地，有16种通过在细胞水平上调p53乙酰化来抑制SIRT1。