RESUMO
High throughput screening using Automated Ligand Identification System (ALIS) resulted in the discovery of a new series of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. The optimization campaign led to very potent and competitive compound 39 with a Ki value of 1.5 nM. Compound 39 could be a promising lead compound for research to reduce elevated homocysteine levels.
Assuntos
Adenosil-Homocisteinase/antagonistas & inibidores , Amidas/farmacologia , Aminas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monometilidrazina/farmacologia , Adenosina/química , Adenosil-Homocisteinase/metabolismo , Amidas/síntese química , Amidas/química , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Monometilidrazina/síntese química , Monometilidrazina/química , Relação Estrutura-AtividadeRESUMO
With the objective of developing new antitumor agents, two groups of hydrazine compounds, having structural features in common with the antitumor agents procarbazine and 1-acetyl-2-picolinoylhydrazine, were synthesized. The L-1210 leukemia system was used to evaluate compounds of both groups. The aliphatic procarbazines also were screened for antitumor activity as bis(benzyloxycarbonyl) derivatives and as derivatives having a phthalazine nucleus. No L-1210 antitumor activity was exhibited by these compounds.