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Bioorg Med Chem ; 21(21): 6565-73, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24026016

RESUMO

In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2ß-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079µM respectively. It is noteworthy that our designed N-phenyl-2ß-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Acetamidas/síntese química , Inibidores Enzimáticos/síntese química , Álcoois Açúcares/química , alfa-L-Fucosidase/antagonistas & inibidores , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/metabolismo , Acetamidas/química , Acetamidas/metabolismo , Animais , Domínio Catalítico , Bovinos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Epididimo/enzimologia , Humanos , Rim/enzimologia , Lisossomos/enzimologia , Masculino , Ligação Proteica , Ratos , Relação Estrutura-Atividade , alfa-L-Fucosidase/metabolismo
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