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

• Published in: Chembiochem : a European journal of chemical biology 2009-04, Vol.10 (6), p.1101-1105
• Main Authors: Rawlings, Amy J, Lomas, Hannah, Pilling, Adam W, Lee, Marvin J.-R, Alonzi, Dominic S, Rountree, J.S. Shane, Jenkinson, Sarah F, Fleet, George W.J, Dwek, Raymond A, Jones, John H, Butters, Terry D
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - pharmacology; Affinity Labels - chemical synthesis; Affinity Labels - chemistry; Affinity Labels - pharmacology; Animals; Chromatography, High Pressure Liquid; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycoside Hydrolase Inhibitors; glycosylation; HL-60 Cells; Humans; imino sugars; Imino Sugars - metabolism; nitrophenyl; oligosaccharides; Oligosaccharides - metabolism; photolabile groups; Rats
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200900025

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.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 (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.