Synthesis and biological characterisation of novel N-alkyl-deoxynojirimycin alpha-glucosidase inhibitors.

Journal article

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.

Authors: Rawlings, A; Lomas, H; Pilling, A; Lee, M; Alonzi, D

• Publication status: Published
• Journal: Chembiochem : a European journal of chemical biology
• Volume: 10
• Issue: 6
• Pages: 1101-1105
• Publication date: 2009-04-01
• DOI: 10.1002/cbic.200900025
• EISSN: 1439-7633
• ISSN: 1439-4227
• Language: English
• Keywords: Chromatography, High Pressure Liquid; Oligosaccharides; Endoplasmic Reticulum; Imino Sugars; Humans; Enzyme Inhibitors; 1-Deoxynojirimycin; Animals; HL-60 Cells; alpha-Glucosidases; Rats; Affinity Labels