Design, Synthesis, and Biological Evaluation of Sirtinol Analogues as Class III Histone/Protein Deacetylase (Sirtuin) Inhibitors

摘要: In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), series sirtinol analogues have been synthesized and the degree inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, SIRT2 vivo with phenotypic assay. Two analogues, namely, 3- 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- p-sirtinol), were 2- to 10-fold more than against SIRT1 enzymes. assay, these two small molecules as sirtinol. Compounds lacking 2-hydroxy group at naphthalene moiety or bearing several modifications benzene 2‘-position aniline portion (carbethoxy, carboxy, cyano) 1.3−13 times less sirtinol, whereas 2‘-carboxamido analogue totally inactive. Both (R)- (S)-sirtinol had similar inhibitory effects on enzymes, demonstrating no enantioselective effect.