Synthesis and biological characterisation of novel N-alkyl-deoxynojirimycin alpha-glucosidase inhibitors.
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.
Rawlings
Amy J
AJ
Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, UK.
Lomas
Hannah
H
Pilling
Adam W
AW
Lee
Marvin J-R
MJ
Alonzi
Dominic S
DS
Rountree
J S Shane
JS
Jenkinson
Sarah F
SF
Fleet
George W J
GW
Dwek
Raymond A
RA
Jones
John H
JH
Butters
Terry D
TD
D017485:1-Deoxynojirimycin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000345:Affinity Labels / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D018922:HL-60 Cells; D006801:Humans; D050111:Imino Sugars / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism; D051381:Rats
D000345:Affinity Labels; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars; D009844:Oligosaccharides; D017485:1-Deoxynojirimycin