RESUMEN

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.

Asunto(s)

Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/química , Acetilación , Dominio Catalítico , Química Farmacéutica/métodos , Diseño de Fármacos , Histona Desacetilasa 6 , Histona Desacetilasas/metabolismo , Histonas/química , Humanos , Ácidos Hidroxámicos/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Piperazina , Piperazinas/química , Isoformas de Proteínas , Tubulina (Proteína)/química