title: Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
abstract: In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2'-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3-13 times less potent than sirtinol, whereas the 2'-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.
authors.affiliation: Dipartimento di Studi Farmaceutici, Istituto Pasteur, Fondazione Cenci Bolognetti, Università degli Studi di Roma "La Sapienza", P. le A. Moro 5, 00185 Roma, Italy. antonello.mai@uniroma1.it
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Siva
authors.initials: S
authors.lastname: Lavu
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pezzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Mariotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Camilloni
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005656:Fungal Proteins / Q000235:genetics; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics; D006801:Humans; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016615:Telomere / Q000201:enzymology
chemical_list: D001549:Benzamides; D005656:Fungal Proteins; D056572:Histone Deacetylase Inhibitors; D009284:Naphthols; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C439060:sirtinol; C087778:SIR2 protein, S cerevisiae; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases