ABSTRACT
Syntheses of aryloxyalkanoic acid hydroxyamides are described, all of which are potent inhibitors of histone deacetylase, some being more potent in vitro than trichostatin A (IC(50)=3 nM). Variation of the substituents on the benzene ring as well as fusion of a second ring have marked effects on potency, in vitro IC(50) values down to 1 nM being obtained.
Subject(s)
Amides/chemistry , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Histone Deacetylase Inhibitors , Amides/chemical synthesis , Amides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylases/chemistry , Humans , Protein Conformation , Structure-Activity RelationshipABSTRACT
The synthesis of a novel series of potent inhibitors of histone deacetylases is described, based on arylsulfinyl-2,4-hexadienoic acid hydroxyamides and their derivatives. In vitro IC(50) values down to 40 nM were obtained, and several compounds showed inhibition of CEM (human leukemic) cell viability with IC(50) of approximately 1.5 microM, comparable to or better than that of suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase currently in clinical trials.
