RESUMO
A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos , Quinolinas , Caspase 3 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis, biological evaluation and structure-activity relationships for a series of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors with IC50 in the range of 3-10 nM have been identified. The most active compound within this series, 7{49} and 7{58}, inhibited caspase-3 with IC50=3 nM.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Caspase 3 , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Estrutura Molecular , Quinolonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Synthesis, biological evaluation, and SAR dependencies for a series of novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline inhibitors of caspase-3 are described. The inhibitory activity of the synthesized compounds is highly dependent on the nature of 4-substituents on the core scaffold. 4-methyl-and 4-phenyl-substituted derivatives, which were the most active compounds within this series, inhibited caspase-3 with IC50 of 23 and 27 nM, respectively.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Morfolinas/síntese química , Pirróis/síntese química , Quinolinas/síntese química , Apoptose/efeitos dos fármacos , Caspase 3 , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Células Jurkat , Morfolinas/química , Morfolinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis, biological evaluation and structure-activity relationships for a series of novel nonpeptide small molecule inhibitors of caspase-3 are described. Among the studied compounds, 8-sulfamide derivatives of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines have been identified as potent inhibitors of caspases-3. The most active compound within this series (8f) inhibited caspase-3 with IC(50)=4 nM.
