RESUMO
A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.
Assuntos
Antioxidantes/farmacologia , Calpaína/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Antioxidantes/síntese química , Encéfalo/efeitos dos fármacos , Calpaína/metabolismo , Dipeptídeos/síntese química , Glioma/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Microssomos/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.
Assuntos
Antioxidantes/síntese química , Calpaína/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Antioxidantes/farmacologia , Calpaína/metabolismo , Furanos/química , Humanos , Concentração Inibidora 50 , Leucina/química , Inibidores de Lipoxigenase/farmacologia , Neuroglia , Relação Estrutura-AtividadeRESUMO
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.