RESUMO
The serine protease urokinase plasminogen activator (uPA) is thought to play a central role in tumor metastasis and angiogenesis. Molecular modeling studies suggest that 5-thiomethylthiopheneamidine inhibits uPA by binding at the S1 pocket of the active site. Further structure based elaboration of this residue resulted in a novel class of potent and selective inhibitors of uPA.
Assuntos
Antimetabólitos/farmacologia , Tiofenos/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Antimetabólitos/síntese química , Antimetabólitos/química , Sítios de Ligação , Humanos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Ativador de Plasminogênio Tipo Uroquinase/fisiologiaRESUMO
Bicyclic thiazolidine lactam peptidomimetics 3-5 have been synthesized as potential analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). Peptidomimetics 3 and 4 were designed to constrain two, psi 2 and phi 3, of the four torsion angles that define a beta-turn to values approximating those found for a type-II beta-turn, while 5 was designed as a compound that could not achieve a beta-turn conformation. Peptidomimetics 3 and 4 were found to enhance the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while 5 was found to be inactive. Like PLG the dose-response curves for 3 and 4 were bell-shaped in nature with the maximum effect occurring at a concentration of 1 microM. Both 3 and 4 were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. The 5,5-bicyclic thiazolidine lactam peptidomimetic 3 enhanced the binding of ADTN by almost 200%, while the 6,5-bicyclic thiazolidine lactam peptidomimetic 4 enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II beta-turn.