Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides.
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).
Bressi
Jerome C
JC
Takeda San Diego, San Diego, CA 92121, USA.
Jennings
Andy J
AJ
Skene
Robert
R
Wu
Yiqin
Y
Melkus
Robert
R
De Jong
Ron
R
O'Connell
Shawn
S
Grimshaw
Charles E
CE
Navre
Marc
M
Gangloff
Anthony R
AR
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D045325:HCT116 Cells; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D013329:Structure-Activity Relationship
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D056464:Histone Deacetylase 2