Volume 10, Issue 6 p. 1101-1105
Full Paper

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

Amy J. Rawlings

Amy J. Rawlings

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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Hannah Lomas

Hannah Lomas

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

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Adam W. Pilling Dr.

Adam W. Pilling Dr.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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Marvin J.-R. Lee

Marvin J.-R. Lee

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

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Dominic S. Alonzi Dr.

Dominic S. Alonzi Dr.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

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J. S. Shane Rountree Dr.

J. S. Shane Rountree Dr.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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Sarah F. Jenkinson Dr.

Sarah F. Jenkinson Dr.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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George W. J. Fleet Prof. Dr.

George W. J. Fleet Prof. Dr.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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Raymond A. Dwek Prof. Dr.

Raymond A. Dwek Prof. Dr.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

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John H. Jones Dr.

John H. Jones Dr.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)

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Terry D. Butters Dr.

Terry D. Butters Dr.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU (UK), Fax: (+44) 1865-275216

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First published: 08 April 2009
Citations: 73

Graphical Abstract

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.

Abstract

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.