Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides

Jerome C Bressi; Andy J Jennings; Robert Skene; Yiqin Wu; Robert Melkus; Ron De Jong; Shawn O'Connell; Charles E Grimshaw; Marc Navre; Anthony R Gangloff

doi:10.1016/j.bmcl.2010.03.091

Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides

Bioorg Med Chem Lett. 2010 May 15;20(10):3142-5. doi: 10.1016/j.bmcl.2010.03.091. Epub 2010 Mar 30.

Authors

Jerome C Bressi¹, Andy J Jennings, Robert Skene, Yiqin Wu, Robert Melkus, Ron De Jong, Shawn O'Connell, Charles E Grimshaw, Marc Navre, Anthony R Gangloff

Affiliation

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

PMID: 20392638
DOI: 10.1016/j.bmcl.2010.03.091

Abstract

A series of N-(2-amino-5-substituted phenyl)benzamides (3-21) were designed, synthesized and evaluated for their inhibition of HDAC2 and their cytotoxicity in HCT116 cancer cells. Multiple compounds from this series demonstrated time-dependent binding kinetics that is rationalized using a co-complex crystal structure of HDAC2 and N-(4-aminobiphenyl-3-yl)benzamide (6).

MeSH terms

Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / toxicity
Binding Sites
Catalytic Domain
Crystallography, X-Ray
HCT116 Cells
Histone Deacetylase 2 / antagonists & inhibitors*
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / toxicity
Humans
Kinetics
Structure-Activity Relationship

Substances

Benzamides
Histone Deacetylase Inhibitors
Histone Deacetylase 2