Synthesis and Biological Characterisation of Novel N-Alkyl-Deoxynojirimycin a-Glucosidase Inhibitors

Illuminating glucosidases: The shown photoaffinity probe for endoplasmic reticulum (ER) -glucosidases was found to be a highly potent inhibitor of -glucosidase I in vitro and equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis. The N-alkylated deoxynojirimycin compound, N-(6-(4-azido-2-nitrophenylamino)hexyl)-1-deoxynojirimycin (6) was synthesised as a potential photoaffinity probe for endoplasmic reticulum (ER) -glucosidases I and II. Surprisingly this compound was a highly potent inhibitor of -glucosidase I (IC50, 17 nM) in an in vitro assay and proved equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis. A modest library of compounds was synthesised to obtain structure-activity information by variation of the N-alkyl chain length and modifications to the azido-nitrophenyl group. All of these compounds failed to improve on the efficacy of compound 6, but most showed greater enzyme inhibitory potency than N-butyl-deoxynojirimycin (NB-DNJ), a pharmacological agent that has been evaluated for the treatment of several viruses for which infectivity is dependent on host cell glycosylation.