1-N-IMINOSUGARS - POTENT AND SELECTIVE INHIBITORS OF BETA-GLYCOSIDASES

A series of 1-N-iminosugars were synthesized to supply the need for gl ycosidase inhibitors that are both highly potent and selective for bet a-glycosidases. Designed on the basis of the transition-state model of the beta-glucosidase reaction, these iminosugar inhibitors differ fro m the currently available inhibitors in possessing a nitrogen atom at the anomeric position of the pyranose ring, thereby generating a posit ive charge on the anomeric position rather than on the ring oxygen of the sugar. Their syntheses, starting with a readily available carbohyd rate derivative, involve (i) introduction of an amino functionality as an azido group, (ii) formation of a 1-N-iminopyranose ring with reduc tive amination, and (iii) stereoselective introduction of a hydroxymet hyl or methyl group and were accomplished in a highly stereoselective and efficient manner. The inhibitory potencies of the 1-N-iminosugars were evaluated against several alpha- and beta-glycosidases, and they were found to be extremely potent and highly specific against the corr esponding beta-glycosidases, with K-i values in the nanomolar range.