RESUMO
We report the discovery of a novel series of 1,5-bisphenylpyrazoles as potent MALT1 inhibitors. Structure-activity relationship exploration of a hit compound led to a potent MALT1 inhibitor. Compound 33 showed strong activity against MALT1 (IC50: 0.49 µM), potent cellular activity (NF-κB inhibition and inhibition of IL2 production), and high selectivity against caspase-3, -8, and -9. The results of a kinetics study suggest that compound 33 is a non-competitive inhibitor of MALT1 protein.
Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Pirazóis/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
A new hexacyclic iboga-type indole alkaloid, voacangalactone (1), was isolated from Voacanga africana , and its structure including the absolute configuration was established by asymmetric total synthesis involving such key steps as the asymmetric Diels-Alder reaction using an aminodiene and the construction of an isoquinuclidine ring and an indole skeleton.