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-(l-phenylethyl)benzamide (i.e., in- 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.

Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (sirtuin) inhibitors / Mai, Antonello; Silvio, Massa; Siva, Lavu; Riccardo, Pezzi; Silvia, Simeoni; Ragno, Rino; Mariotti, FRANCESCA ROMANA; Chiani, Francesco; Camilloni, Giorgio; David A., Sinclair. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48:24(2005), pp. 7789-7795. [10.1021/jm050100l]

Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (sirtuin) inhibitors

MAI, Antonello;RAGNO, Rino;MARIOTTI, FRANCESCA ROMANA;CHIANI, Francesco;CAMILLONI, Giorgio;
2005

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-(l-phenylethyl)benzamide (i.e., in- 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.
2005
01 Pubblicazione su rivista::01a Articolo in rivista
Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (sirtuin) inhibitors / Mai, Antonello; Silvio, Massa; Siva, Lavu; Riccardo, Pezzi; Silvia, Simeoni; Ragno, Rino; Mariotti, FRANCESCA ROMANA; Chiani, Francesco; Camilloni, Giorgio; David A., Sinclair. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48:24(2005), pp. 7789-7795. [10.1021/jm050100l]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/364994
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