Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Eur J Med Chem. 2013 Feb;60:441-50. doi: 10.1016/j.ejmech.2012.12.026. Epub 2012 Dec 20.
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 是一种依赖 NAD(+)的去乙酰化酶。在这里，我们描述了以苯并呋喃-3-基（苯基）甲酮为骨架的新型 SIRT1 抑制剂。抑制剂被预测与 SIRT1 的 C 口袋结合，与 Phe273、Phe312 和 Ile347 形成疏水相互作用。在苯基的间位引入羟基可能与 Asn346 形成氢键。事实上，（2,5-二羟基苯基）（5-羟基-1-苯并呋喃-3-基）甲酮（16），一个在邻位和间位都有羟基的类似物，表现出更强的抑制作用。通过结构修饰和动力学研究验证了结合模式。由于 C 口袋是烟酰胺部分结合和水解发生的部位，16 在 C 口袋中的结合会阻止 NAD(+)转化为有效构象，从而抑制去乙酰化酶活性。一致地，16 通过在细胞水平上上调 p53 乙酰化来抑制 SIRT1。
