Novel thiourea-based sirtuin inhibitory warheads

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3319-24. doi: 10.1016/j.bmcl.2015.05.058. Epub 2015 May 30.

Abstract

N(ε)-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism-based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N(ε)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(ε)-methyl-thiocarbamoyl-lysine and N(ε)-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N(ε)-methyl-thiocarbamoyl-lysine was found in the study to be a ∼ 2.5-18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N(ε)-thiocarbamoyl-lysine.

Keywords: Deacetylation; Deacylation; Inhibitory warhead; N(ε)-Carboxyethyl-thiocarbamoyl-lysine; N(ε)-Methyl-thiocarbamoyl-lysine; SIRT1; SIRT2; SIRT3; SIRT5; Sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Structure
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 2 / antagonists & inhibitors*
  • Thiourea / chemistry*
  • Thiourea / pharmacology

Substances

  • Enzyme Inhibitors
  • Sirtuin 1
  • Sirtuin 2
  • Thiourea