Glycosidases (glycoside hydrolases) are a large family of enzymes that catalyze the hydrolytic degradation of polysaccharides and the maturation of glycoconjugates. Their inhibition constitute an attractive therapeutic approach for the treatment of various diseases. Due to the ubiquity of glycosidases, one of the main research challenges for the development of new drugs acting as glycosidase inhibitors is to design molecules which are selective inhibitors of a specific type of glycosidases. Our team has identified a new class of bicyclic iminosugars with a quaternary center at the ring junction, exhibiting potency at nanomolar concentrations and outstanding selectivity against GH31 ?-glucosidases. In order to expand our library of compounds and unveil their mode of interaction with ?–glucosidases, the objective of this thesis was firstly to develop synthetic routes towards quinolizidine and conidine iminosugars bearing a hydroxymethyl substituent at the ring junction, and secondly to study their interactions with different glycosidases.

Five polyhydroxylated quinolizidines and four polyhydroxylated conidines were obtained from the same L-sorbose-derived ketonitrone. The key steps in the synthesis of quinolizidines are a diastereoselective C-allylation of this nitrone and a ring-closing olefin metathesis. The polyhydroxylated conidines were synthesized from bicyclic ?-lactams, obtained either by a 1,3-dipolar cycloaddition followed by rearrangement of the formed isoxazolines (DeShong method) or by the Kinugasa reaction. The inhibitory potency of these iminosugars was evaluated on a panel of commercial and on human glycosidases. Most of them are selective inhibitors of ?-glucosidases. Conformational studies by NMR and DFT calculations, as well as crystallographic studies of iminosugar/?-glucosidase complexes, clarified the mode of interaction of our new family of iminosugars with these enzymes.