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D-glucosylated derivatives of isofagomine and noeuromycin and their potential as inhibitors of beta-glycoside hydrolases

TitleD-glucosylated derivatives of isofagomine and noeuromycin and their potential as inhibitors of beta-glycoside hydrolases
Publication TypeJournal Article
Year of Publication2007
AuthorsMeloncelli, PJ, Gloster, TM, Money, VA, Tarling, CA, Davies, GJ, Withers, SG, Stick, RV

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-beta-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-beta-D-glucopyranosylnoeuromycin, the former by a selective glycosylation (at O2) of benzyl 4-C-cyano-4-deoxy-beta-D-arabinoside (also leading to another synthesis of 3-O-beta-D-glucopyranosylisofagomine), the latter by a non-selective glycosylation of benzyl 4-O-allyl-beta- xyloside with subsequent introduction of the required nitrile group (also leading to another synthesis of 4-O-beta-D-glucopyranosylisofagomine). 3-O-beta-D-Glucopyranosylnoeuromycin was evaluated as an inhibitor of a family 26 lichenase from Clostridium thermocellum, and 4-O-beta-D-glucopyranosylnoeuromycin as an inhibitor of both a family 5 endoglucanase from Bacillus agaradhaerans and a family 10 endo-xylanase from Cellulomonas fimi. We also report X-ray structural investigations of 3- and 4-O-beta-D-glucopyranosylnoeuromycin in complex with the family 26 and family 5 beta-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.