Synthesis and Biological Characterisation of Novel N‐Alkyl‐Deoxynojirimycin α‐Glucosidase Inhibitors

Illuminating glucosidases : The shown photoaffinity probe for endoplasmic reticulum (ER) α‐glucosidases was found to be a highly potent inhibitor of α‐glucosidase I in vitro and equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis. magnified image 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) α‐glucosidases I and II. Surprisingly this compound was a highly potent inhibitor of α‐glucosidase I (IC 50 , 17 n M ) 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 ( N B‐DNJ), a pharmacological agent that has been evaluated for the treatment of several viruses for which infectivity is dependent on host cell glycosylation.