Conformational behavior of aza-C-glycosides: Experimental demonstration ofthe relative role of the exo-anomeric effect and 1,3-type interactions in controlling the conformation of regular glycosides

The conformational behavior of different: aza-C-glycosides synthesized as g lycosidase inhibitors has been studied using a combination of NMR spectrosc opy (J and NOE data) and time-averaged restrained molecular dynamics calcul ations. The obtained results show that the population distribution of confo rmers around their pseudoglycosidic Linkages is mainly controlled by 1,3-sy n-diaxial interactions. Electrostatic effects slightly modulate the conform ational equilibrium. This result is in contrast with that observed for O-gl ycosides. For these natural compounds, the conformational behavior around t he glycosidic linkage Phi is mainly governed by the exo-anomeric effect. Ex perimentally based energy values for both the 1,3-syn-diaxial interactions and the stereoelectronic effect have been deduced. Finally, the inhibitory activity of these compounds has been tested again a variety of glycosidase enzymes.