Gas-phase structure and conformation of the glycosidase and ceramide glucosyltransferase inhibitor N-benzyl deoxynojirimycin

The deoxynojirimycin (DNJ) family of imino sugars are glucose analogues with an NH group replacing the oxygen atom in the pyranose ring. They are powerful inhibitors of glycosidases and ceramide glucosyltransferases. The conformation of N-benzyl-DNJ, isolated in the gas phase, is studied using a combination of resonant two-photon ionization (R2PI), UV/UV hole-burn, and IR ion-dip spectroscopies in conjunction with electronic structure theory calculations. Three distinct conformers, one major and two minor, are present and all three are assigned to structures in which the exocyclic hydroxymethyl group is axial to the piperidine ring (gauche- to the ring nitrogen). This contrasts with the preferred equatorial (gauche+) orientation observed for simple glucosides and may well contribute to the stronger binding of some enzymes to DNJ-based inhibitors compared to their natural glucoside substrates.