N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: design, synthesis, SAR studies, and in vivo antitumor activity

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1403-8. doi: 10.1016/j.bmcl.2009.01.041. Epub 2009 Jan 19.

Abstract

A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.

Publication types

  • Comparative Study

MeSH terms

  • Acrylamides / administration & dosage
  • Acrylamides / chemical synthesis*
  • Acrylamides / pharmacology
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor / methods
  • Female
  • HCT116 Cells
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Acrylamides
  • Antineoplastic Agents
  • Benzimidazoles
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases