Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors.
J Med Chem
; 48(24): 7789-95, 2005 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-16302818
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.
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Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Sirtuínas
/
Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae
/
Inibidores de Histona Desacetilases
/
Naftóis
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article