RESUMO
The known KDR inhibitor SU5416 and several analogues of the indolin-2-one family were surprisingly found to be highly efficacious in the EAE model, an established model for multiple sclerosis. The high in vivo effect could be correlated to in vitro inhibition of the pro-inflammatory cytokine IL-2. Activity following po administration was obtained with several analogues and via the use of prodrugs.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Indóis/síntese química , Esclerose Múltipla/metabolismo , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Esclerose Múltipla/tratamento farmacológico , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Syntheses of racemic forms of the main secondary metabolites of Quararibea funebris, (+/-)-funebrine, (+/-)-funebral, and their biogenetic precursor (+/-)-(2S,3S,4R)-gamma-hydroxyalloisoluecine lactone have been developed. In synthetic studies, a new variation of the Paal-Knorr condensation employing titanium isopropoxide was utilized to construct the pyrrole lactone moiety. Two efficient synthetic approaches to the key (+/-)-gamma-amino lactone have been developed, one based on Claisen chemistry and the other on addition reactions to the butenolide ring of beta-angelicalactone. The restricted rotation around the C(sp(3))-N(sp(2)) bond in the pyrrole lactone structures of (+/-)-funebrine, (+/-)-funebral, and related aldehydes has been probed by conformational dynamic studies, and the barriers for interconversion between conformations have been measured by full NMR line-shape analysis. Molecular mechanics (MMX) and a (1)H-(1)H NOE study indicate a distinct preferred conformation for (+/-)-funebrine.