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Synthesis and Biological Characterisation of Novel N ‐Alkyl‐Deoxynojirimycin α‐Glucosidase Inhibitors
Author(s) -
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.
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200900025
Subject(s) - glucosidases , endoplasmic reticulum , oligosaccharide , chemistry , glycosylation , biochemistry , enzyme , in vitro , alkylation , stereochemistry , catalysis
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 (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.