ABSTRACT
Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24h following a single dose.
Subject(s)
Benzoxazines/chemistry , Benzoxazines/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Cell Line, Tumor , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Nude , Molecular StructureABSTRACT
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.
Subject(s)
Benzimidazoles/chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Imidazoles/chemistry , Acetylation , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Cell Line, Tumor , HL-60 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Mice , Mice, Nude , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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).
Subject(s)
Benzamides/chemistry , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/chemical synthesis , Benzamides/chemical synthesis , Benzamides/toxicity , Binding Sites , Catalytic Domain , Crystallography, X-Ray , HCT116 Cells , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/toxicity , Humans , Kinetics , Structure-Activity RelationshipABSTRACT
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
