Synthesis and Biological Characterisation of Novel N-Alkyl-Deoxynojirimycin α-Glucosidase Inhibitors
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-alky...
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| Veröffentlicht in: | Chembiochem : a European journal of chemical biology 2009-04, Vol.10 (6), p.1101-1105 |
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| container_title | Chembiochem : a European journal of chemical biology |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1002/cbic.200900025 |
| format | Article |
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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.</description><identifier>ISSN: 1439-4227</identifier><identifier>EISSN: 1439-7633</identifier><identifier>DOI: 10.1002/cbic.200900025</identifier><identifier>PMID: 19294724</identifier><language>eng</language><publisher>Weinheim: Wiley-VCH Verlag</publisher><subject>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</subject><ispartof>Chembiochem : a European journal of chemical biology, 2009-04, Vol.10 (6), p.1101-1105</ispartof><rights>Copyright © 2009 WILEY‐VCH Verlag GmbH & Co. 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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. 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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.</abstract><cop>Weinheim</cop><pub>Wiley-VCH Verlag</pub><pmid>19294724</pmid><doi>10.1002/cbic.200900025</doi><tpages>5</tpages></addata></record> |
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| 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 |
| title | Synthesis and Biological Characterisation of Novel N-Alkyl-Deoxynojirimycin α-Glucosidase Inhibitors |
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