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

Abstract

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) alpha-glucosidases I and II. Surprisingly this compound was a highly potent inhibitor of alpha-glucosidase I (IC(50), 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.

New N-(phenoxydecyl)phthalimide derivatives displaying potent inhibition activity towards α-glucosidase

“…Finally, it is noteworthy that compound 20x showed an activity comparable to that of the best compounds of the series (20q,r,s), outlying the importance of the simultaneous presence of at least a chlorine atom and a strong electron-withdrawing group, such as a nitro group, at the phenoxy moiety. Notably, these results are in agreement with those recently reported in the literature by Rawlings et al 23 which identified a dNM derivative, bearing a nitro substituted phenyl moiety, as the best a-glucosidase inhibitor reported to date. The most potent compounds of the series (20q,r,s,x) concerned for b-glucosidase, a-mannosidase, and a-galactosidase showed no inhibition activity at the maximal tested concentration of 25 lM (i.e., two orders of magnitude higher than IC 50 values observed for a-glucosidase).…”

Novel pyridine-2,4,6-tricarbohydrazide derivatives: Design, synthesis, characterization and in vitro biological evaluation as α- and β-glucosidase inhibitors

“…a-Glucosidase inhibitors are also known for their antitumor, anti-viral and immunoregulatory activities [7][8][9][10]. From a-glucosidase inhibitors, deoxynojirimycin (DNJ), Nbutyl-deoxynojirimycin (NB-DNJ) and castanospermine are known to be potent inhibitors of both HIV replication and HIV mediated syncytium development [9].…”

Synthetic 1‐Deoxynojirimycin N‐Substituted Peptides Offer Prolonged Disruption to N‐Linked Glycan Processing

“…Man 3 GlcNAc 1 (t R~2 1.0 min) was used as an internal standard (IS) because it is a lysosomal degradation product that remains unaffected by treatment with a-glucosidase inhibitors, as we previously reported. [24,25] While FOS analysis is a useful tool for studying N-linked glycan processing, its analysis is complicated owing to the network of simultaneous enzymatic reactions that impact glycan processing. However, what is clear in the inhibitor concentration range studied is that the N-substituted peptides 2 a,b and d are selective inhibitors of ER GluII, as no triglucosylated species arising from inhibition of GluI were detected.…”