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J Med Chem ; 55(15): 6802-13, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22849615

RESUMO

Overexpression of human GSTA1-1 in tumor cells is part of MDR mechanisms. We report on the synthesis of 11 pyrrole derivatives as hGSTA1-1 inhibitors starting from 1-methyl-2-[(2-nitrobenzylsulfanyl]-1H-pyrrole. Molecular modeling revealed two locations in the enzyme H binding site: the catalytic primary one accommodating shorter and longer derivatives and the secondary one, where shorter derivatives can occupy. Derivative 9, displaying the highest inhibition and bearing a p-nitroarylimino moiety, and derivative 4, lacking this moiety, were studied kinetically. Derivative 9 binds (K(i(9)) = 71 ± 4 µM) at the primary site competitively vs CDNB. Derivative 4 binds (K(i(4)) = 135 ± 27 µM) at the primary and secondary sites, allowing the binding of a second molecule (4 or CDNB) leading to formation of unreactive and reactive complexes, respectively. The arylmethylsulfonylpyrrole core structure is a new pharmacophore for hGSTA1-1, whereas its derivative 9 may serve as a lead structure.


Assuntos
Compostos de Anilina/síntese química , Glutationa Transferase/antagonistas & inibidores , Iminas/síntese química , Isoenzimas/antagonistas & inibidores , Pirróis/síntese química , Sulfonas/síntese química , Compostos de Anilina/química , Ensaios Enzimáticos , Glutationa Transferase/química , Humanos , Iminas/química , Isoenzimas/química , Cinética , Modelos Moleculares , Ligação Proteica , Pirróis/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química
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