RESUMO
A series of novel hydroxamic acid based histone deacetylases (HDAC) inhibitors with aryl ether and aryl sulfone residues at the terminus of a substituted, unsaturated 5-carbon spacer moiety have been synthesized for the first time and evaluated. Compounds with meta- and para-substitution on the aryl ring of ether hydroxamic acids 19c, 20c, 19e, 19f and 19g are potent HDAC inhibitors with activities at low nanomolar levels.
Assuntos
Éteres/química , Inibidores de Histona Desacetilases/síntese química , Ácidos Hidroxâmicos/química , Sulfonas/química , Sítios de Ligação , Domínio Catalítico , Desenho de Fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
[structure: see text]. An efficient three-step synthesis of chiral 3H-quinazoline-4-one derivatives from commercial materials is disclosed. The Mumm reaction of imidoyl chloride with alpha-amino acids followed by reductive cyclization affords enantiomerically pure (ee >93%) quinazoline-4-ones in good overall yield. A comparison with existing approaches indicates that this method is superior for hindered substrates.