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Bioorg Med Chem Lett ; 24(14): 3026-33, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24881567

RESUMO

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.


Assuntos
Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteína bcl-X/metabolismo
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