RESUMO
We present a convenient synthesis of novel heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides and 5-oxo-1,4-thiazepine-3-carboxamides using a modification of four-component Ugi condensation. We demonstrate the usefulness and versatility of the developed approach for the synthesis of variously substituted compounds and discuss the scope and limitations of the chemistry involved.
Assuntos
Carbamatos/química , Tiazepinas/síntese química , Estrutura Molecular , Estereoisomerismo , Tiazepinas/químicaRESUMO
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.