Synthesis and biological evaluation of N-(2-fluorophenyl)-2β-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases.

Abstract 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)-2β-DFJ acetamide ( 18j ) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α- l -fucosidases, with IC 50 value of 0.012, 0.044, and 0.0079 μM respectively. It is noteworthy that our designed N -pheny l -2β-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.