Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
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.
Mai
Antonello
A
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
Massa
Silvio
S
Lavu
Siva
S
Pezzi
Riccardo
R
Simeoni
Silvia
S
Ragno
Rino
R
Mariotti
Francesca R
FR
Chiani
Francesco
F
Camilloni
Giorgio
G
Sinclair
David A
DA
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
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