RESUMO
The synthesis and biochemical characterization of AX4697, a fluorescent, bisindolylmaleimide-derived probe for PKCalpha and beta, is described. AX4697 was able to quantify changes in PKC expression in drug-treated Jurkat cells and was shown to covalently label PKCalpha on C619, a residue that sits just outside the active site.
Assuntos
Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Indóis/síntese química , Indóis/farmacologia , Maleimidas/síntese química , Maleimidas/farmacologia , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C/metabolismo , Domínio Catalítico , Desenho de Fármacos , Corantes Fluorescentes/química , Humanos , Indóis/química , Células Jurkat , Maleimidas/química , Estrutura Molecular , Proteína Quinase C beta , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against three dipeptidyl peptidases (DPPs) was studied. In a series of N-cycloalkyl analogs, DPP4 and fibroblast activation protein-alpha (FAP) optimally preferred N-cycloheptyl whereas DPP7 tolerated even larger cycloalkyl rings. Gly alpha-carbon derivatization of N-cyclohexyl or N-(2-adamantyl) Gly-boro-Pro resulted in a significant decrease in potency against all the three DPPs.
Assuntos
Dipeptídeos/síntese química , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Inibidores de Adenosina Desaminase , Antígenos de Neoplasias , Biomarcadores Tumorais/antagonistas & inibidores , Ácidos Borônicos , Dipeptídeos/farmacologia , Dipeptidil Peptidase 4 , Endopeptidases , Gelatinases , Glicoproteínas/antagonistas & inibidores , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacologia , Concentração Inibidora 50 , Proteínas de Membrana , Serina Endopeptidases , Relação Estrutura-AtividadeRESUMO
A novel series of inhibitors that contain an aryl alpha,alpha-difluoro-beta-ketophosphonate group has been synthesized and evaluated against protein tyrosine phosphatase 1B. These compounds exhibit strong inhibitory activity, the best of which has a K(i) value of 0.17 microM. These results demonstrate that aryl alpha,alpha-difluoro-beta-ketophosphonates are powerful phosphotyrosine mimetics for the development of potent PTP inhibitors.