d-Glyconhydroximolactams strongly inhibit α-glycosidases

It has been postulated that proton transfer to β-glycosides by some retaining β-glycosidases takes place in the plane of the pyranoside ring. It is now hypothesised that a similarly oriented catalytically active acidic group in α-glycosidases could interact with glyconolactone derivatives, provided that these are sufficiently basic to overcome the effect of a less favourable geometry by an energetically more favourable interaction. In keeping with this hypothesis, d-glyconolactone, d-gluconolactam, the tetrazole 3, and the hydroximolactone 5 are weak inhibitors of yeast α-glucosidase, while the hydroximolactam 6 (pKa = 4.8) is a mixed-type (α = 2) strong inhibitor (Ki = 2.9 μM). A similar inhibition is observed for the arylcarbamoyl derivative 9, while the (methylthio)methyl derivative 10 inhibits more weakly and in a purely competitive fashion. The mannonhydroximolactam 11 strongly inhibits jack bean α-mannosidase (Ki = 0.15 μM), while the gluco analogue 6 inhibits about 80 times more weakly, illustrating the dependence upon configuration.