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

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

doi:10.1071/CH07188

RESEARCH ARTICLE

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 and Robert V. Stick ^A ^D

+ Author Affiliations

- Author Affiliations

^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

Australian Journal of Chemistry 60(8) 549-565 https://doi.org/10.1071/CH07188
Submitted: 4 June 2007 Accepted: 27 June 2007 Published: 9 August 2007

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.

Acknowledgments

Carlos Fontes (Lisbon) and Harry Gilbert (Newcastle) and their research groups are thanked for inspiration and provision of resources for the CtLic26 work. The Biotechnology and Biological Sciences Research Council (BBSRC) and the Canadian Institutes for Health Research (CIHR) are thanked for funding. G.J.D. is the recipient of a Royal Society–Wolfson Research Merit Award.

References

^* According to IUPAC recommendations, ‘Use of the terms ‘aza sugar’, ‘phospha sugar’, etc. should be restricted to structures where carbon, not oxygen, is replaced by a heteroatom. The term ‘imino sugar’ may be used as a class name for cyclic sugar derivatives in which the ring oxygen atom has been replaced by nitrogen.

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

Abstract

Acknowledgments

Subscriber Login