Novel Cambinol analogs as Sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity

Federico Medda, Rupert James Martin Russell, Maureen Higgins, Anna Rose McCarthy, Johanna Campbell, Alexandra Martha Zoya Slawin, David Lane, Sonia Lain, Nicholas James Westwood

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)

Abstract

The tenovins and cambinol are two classes of sirtuin inhibitor that exhibit antitumor activity in preclinical models. This report describes modifications to the core structure of cambinol, in particular by incorporation of substitutents at the N1-position, which lead to increased potency and modified selectivity. These improvements have been rationalized using molecular modeling techniques. The expected functional selectivity in cells was also observed for both a SIRT1 and a SIRT2 selective analog.

Original languageEnglish
Pages (from-to)2673-2682
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number9
Early online date1 Apr 2009
DOIs
Publication statusPublished - 14 May 2009

Keywords

  • Small-Molecule Inhibitor
  • P53
  • SIR2
  • Deacetylase
  • Binding
  • Survival
  • Homolog
  • Disease
  • Enzymes
  • Mice

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