3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2)

Soo Hyuk Choi, Luisa Quinti, Aleksey G. Kazantsev, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)- N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.

Original languageEnglish (US)
Pages (from-to)2789-2793
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number8
DOIs
StatePublished - Apr 15 2012

Keywords

  • 3-(N-Arylsulfamoyl)benzamides
  • Hydrophobic pocket
  • Neurodegenerative disease
  • Sirtuin 2
  • Sirtuin selectivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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