RESUMO
This study details the development of matrix metalloproteinase inhibitor prodrugs (proMMPi) that are activated in the presence of reactive-oxygen species (ROS). Conventional matrix metalloproteinase inhibitors (MMPi) utilize a zinc-binding group (ZBG) that chelates to the catalytic zinc(II) ion of matrix metalloproteinases (MMPs) to inhibit their activity. To create ROS-sensitive prodrugs, sulfonate esters were used as a protecting group for the ZBG to block their metal binding ability. Surprisingly, these sulfonate esters were found to be cleaved by H(2)O(2) only when the ZBG contained an N-oxide donor atom moiety. Sulfonate ester derivatives of full-length MMPi based on these ROS-triggerable systems were synthesized. It was found that proMMPi with sulfonate ester protecting groups showed relatively high rates of cleavage in the presence of H(2)O(2) to release the active MMPi. In vitro MMP inhibition studies confirmed a significant increase in inhibitory activity of proMMPi upon addition of H(2)O(2), demonstrating the use of sulfonate esters to act as cleavable triggers for ROS-activated prodrugs.
Assuntos
Ativação Enzimática/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/metabolismo , Pró-Fármacos , Espécies Reativas de Oxigênio/metabolismoAssuntos
Inibidores Enzimáticos/química , Peróxido de Hidrogênio/metabolismo , Inibidores de Metaloproteinases de Matriz , Pró-Fármacos/química , Piridonas/química , Barreira Hematoencefálica/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Piridonas/síntese química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Matrix metalloproteinase inhibitors (MMPi) possessing a glucose protecting group on the zinc-binding group (ZBG) show a dramatic increase in inhibitory activity upon cleavage by beta-glucosidase.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , beta-Glucosidase/metabolismo , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Inibidores de Proteases/metabolismoRESUMO
This short review highlights some recent advances in matrix metalloproteinase inhibitor (MMPi) design and development. Three distinct approaches to improved MMP inhibition are discussed: (1) the identification and investigation of novel zinc-binding groups (ZBGs), (2) the study of non-zinc-binding MMPi, and (3) mechanism-based MMPi that form covalent adducts with the protein. Each of these strategies is discussed and their respective advantages and remaining challenges are highlighted. The studies discussed here bode well for the development of ever more selective, potent, and well-tolerated MMPi for treating several important disease pathologies.
