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Article << Previous     |     Next >>   Contents Vol 60(8)

d-Glucosylated Derivatives of Isofagomine and Noeuromycin and Their Potential as Inhibitors of β-Glycoside Hydrolases

Peter J. Meloncelli A, Tracey M. Gloster B, Victoria A. Money B, Chris A. Tarling C, Gideon J. Davies B, Stephen G. Withers C, Robert V. Stick A D

A Chemistry M313, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley WA 6009, Australia.
B Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, YO10 5YW, UK.
C Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1, Canada.
D Corresponding author. Email: rvs@chem.uwa.edu.au
 
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Abstract

While isofagomine and noeuromycin have previously been demonstrated to be effective inhibitors of a range of exo-acting glycosidases, they are usually only very weak inhibitors of endo-glycosidases. However, the disaccharide-like 3- and 4-O-β-d-glucopyranosylisofagomines have proven to be strong inhibitors of these endo-acting enzymes that utilize multiple sub-sites. In an attempt to emulate these successes, we have prepared 3- and 4-O-β-d-glucopyranosylnoeuromycin, the former by a selective glycosylation (at O2) of benzyl 4-C-cyano-4-deoxy-α-d-arabinoside (also leading to another synthesis of 3-O-β-d-glucopyranosylisofagomine), the latter by a non-selective glycosylation of benzyl 4-O-allyl-β-l-xyloside with subsequent introduction of the required nitrile group (also leading to another synthesis of 4-O-β-d-glucopyranosylisofagomine). 3-O-β-d-Glucopyranosylnoeuromycin was evaluated as an inhibitor of a family 26 lichenase from Clostridium thermocellum, and 4-O-β-d-glucopyranosylnoeuromycin as an inhibitor of both a family 5 endo-glucanase from Bacillus agaradhaerans and a family 10 endo-xylanase from Cellulomonas fimi. We also report X-ray structural investigations of 3- and 4-O-β-d-glucopyranosylnoeuromycin in complex with the family 26 and family 5 β-glycoside hydrolases, respectively. The two d-glucosylated noeuromycins were indeed able to harness the additional binding energy from the sub-sites of their endo-glycoside hydrolase targets, and were thus excellent inhibitors (in the nanomolar range), binding as expected in the –1 and –2 sub-sites of the enzymes.

   
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