RESUMO
We synthesized a series of delta-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated anti-inflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-alpha and nitric oxide by LPS-stimulated RAW264.7 cells.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Inibidores de Histona Desacetilases , Lactamas/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactamas/química , Lactamas/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Moleculares , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade , Transplante Heterólogo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
delta-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell.
