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

J Med Chem. 2005 Dec 1;48(24):7789-95. doi: 10.1021/jm050100l.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Drug Design
  • Fungal Proteins / genetics
  • Gene Silencing
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Humans
  • Naphthols / chemical synthesis*
  • Naphthols / chemistry
  • Naphthols / pharmacology
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / antagonists & inhibitors*
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / chemistry
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / genetics
  • Sirtuin 1
  • Sirtuin 2
  • Sirtuins / antagonists & inhibitors*
  • Sirtuins / chemistry
  • Sirtuins / genetics
  • Stereoisomerism
  • Structure-Activity Relationship
  • Telomere / enzymology

Substances

  • Benzamides
  • Fungal Proteins
  • Histone Deacetylase Inhibitors
  • Naphthols
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • sirtinol
  • SIR2 protein, S cerevisiae
  • SIRT1 protein, human
  • SIRT2 protein, human
  • Sirtuin 1
  • Sirtuin 2
  • Sirtuins
  • Histone Deacetylases