Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

Bioorg Med Chem. 2014 Jan 15;22(2):703-10. doi: 10.1016/j.bmc.2013.12.029. Epub 2013 Dec 19.

Abstract

A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.

Keywords: Anti-proliferative; Benzimidazole; Breast cancer; Electron donating; Sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 1 / metabolism
  • Sirtuin 2 / antagonists & inhibitors*
  • Sirtuin 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • benzimidazole
  • SIRT1 protein, human
  • SIRT2 protein, human
  • Sirtuin 1
  • Sirtuin 2