Abstract
In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
MeSH terms
-
Acetylation
-
Catalytic Domain
-
Chemistry, Pharmaceutical / methods
-
Drug Design
-
Enzyme Inhibitors / chemistry*
-
Histone Deacetylase 6
-
Histone Deacetylase Inhibitors*
-
Histone Deacetylases / chemistry*
-
Histone Deacetylases / metabolism
-
Histones / chemistry
-
Humans
-
Hydroxamic Acids / pharmacology
-
Inhibitory Concentration 50
-
Models, Chemical
-
Piperazine
-
Piperazines / chemistry
-
Protein Isoforms
-
Tubulin / chemistry
Substances
-
Enzyme Inhibitors
-
Histone Deacetylase Inhibitors
-
Histones
-
Hydroxamic Acids
-
Piperazines
-
Protein Isoforms
-
Tubulin
-
Piperazine
-
HDAC6 protein, human
-
Histone Deacetylase 6
-
Histone Deacetylases