RESUMO
A one-pot Yb(III)-mediated cascade reaction has been developed leading to small molecules based on a novel structural motif, i.e. quinazolin-4-one moiety fused with an isoquinoline ring, for potential inhibition of TNF-α.
Assuntos
Mesilatos/química , Compostos Organometálicos/química , Quinazolinonas/química , Quinazolinonas/síntese química , Catálise , Quinazolinonas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Concurrent construction of five and six membered fused N-heretocyclic ring was achieved via a conceptually new three-component reaction affording 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-αin vitro. This represents one of the few examples of direct TNF-α inhibition by small molecules.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Química Verde , Compostos Heterocíclicos/farmacologia , Isoindóis/farmacologia , Quinazolinas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Isoindóis/química , Isoindóis/uso terapêutico , Quinazolinas/síntese química , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Azadirone 1, a limonoidal constituent of Azadirachta indica is found to possess potent cytotoxic activity against a panel of human cancer cell lines in our in vitro studies. In vitro screening of a number of semi-synthetic analogues of 1 revealed that the alpha,beta-unsaturated enone moiety or its equivalent conjugated system in A-ring, C-7 acetyloxy/chloroacetyloxy or keto group in B-ring and the furan moiety are responsible for the activity of 1 and its analogues. Compound 1 and two of the semi-synthetic analogues 10 and 13 were found to possess good in vivo antitumor activity in modified hollow fiber animal models.