RESUMO
Dipeptide-based inhibitors with C-substituted (alkyl or aminoalkyl) alpha-amino acids in the P2 position and boro-norleucine (boro-Nle) in the P1 position were synthesized. Relative to boro-proline, boro-Nle as a P1 residue was shown able to significantly dial out DPP4, FAP, DPP8, and DPP9 activity. Dab-boro-Nle (4g) proved to be the most selective and potent DPP7 inhibitor with a DPP7 IC50 value of 480 pM.
Assuntos
Ácidos Borônicos , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Norleucina/análogos & derivados , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Norleucina/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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
[structure: see text] The synthesis of a photoaffinity probe for EGFR is described. O-Alkylation of 4-(meta-azidoanilino)-6-methoxy-7-hydroxy-quinazoline with a protected tetraethyleneglycol linker followed by the attachment of tetramethylrhodamine yielded the fluorescent probe AX7593. Photoaffinity labeling of EGFR by AX7593 (K(b) = 280 nM) was shown to have an efficiency of 34% and to be competitive with the EGFR inhibitors PP2 and AG1478.
Assuntos
Receptores ErbB/química , Marcadores de Fotoafinidade/síntese química , Quinazolinas/química , Marcadores de Fotoafinidade/química , Quinazolinas/síntese químicaRESUMO
The design and synthesis of AX7574, a microcystin-derived probe for serine/threonine phosphatases, is described. A key step in the synthesis was the conjugation under basic conditions of a tetramethylrhodamine 1,3-diketone derivative to the arginine side chain present in microcystin-LR. The resulting conjugate specifically labeled the active site of protein phosphatases 1 (PP-1) with a 1:1 stoichiometry and IC50 of 4.0 nM. AX7574 was used to isolate and identify PP-1, PP-2A, PP-4, and PP-6 in Jurkat cells. Finally, AX7574 was able to record changes in the phosphatase activity levels of calyculin A treated Jurkat cells versus untreated control cells.
