Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity

Jerome C Bressi; Ron de Jong; Yiqin Wu; Andy J Jennings; Jason W Brown; Shawn O'Connell; Leslie W Tari; Robert J Skene; Phong Vu; Marc Navre; Xiaodong Cao; Anthony R Gangloff

doi:10.1016/j.bmcl.2010.03.092

Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity

Bioorg Med Chem Lett. 2010 May 15;20(10):3138-41. doi: 10.1016/j.bmcl.2010.03.092. Epub 2010 Mar 30.

Authors

Jerome C Bressi¹, Ron de Jong, Yiqin Wu, Andy J Jennings, Jason W Brown, Shawn O'Connell, Leslie W Tari, Robert J Skene, Phong Vu, Marc Navre, Xiaodong Cao, Anthony R Gangloff

Affiliation

¹ Takeda San Diego, San Diego, CA 92121, USA.

PMID: 20392637
DOI: 10.1016/j.bmcl.2010.03.092

Abstract

A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC(50)s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21(waf). Compound 5x displays efficacy in human tumor xenograft models.

MeSH terms

Acetylation
Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacology
Cell Line, Tumor
HL-60 Cells
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology
Mice
Mice, Nude
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Benzimidazoles
Histone Deacetylase Inhibitors
Imidazoles
imidazole
Histone Deacetylases