The potent and selective inhibition of glycosidases is an important goal for the development of therapeutics. Glycosidases cleave the glycosidic bonds in oligosaccharides and glycoconjugates. Their blocking can aid in the treatment of diabetes, viral infections, lysosomal storage diseases, and cancer. Iminosugars have been shown to be highly effective inhibitors but their limited selectivity can lead to side effects when applied therapeutically. It is clear that improving the selectivity of iminosugars as glycosidase inhibitors is an important goal. The effectiveness of the iminosugar as a glycosidase inhibitor in many cases depends on its ability to mimic the relevant transition state in the cleavage process. The mimicry depends on the complementarity with respect to charge and shape. These issues are intimately linked to the hybridization state (sp2) of the ‘anomeric carbon’ and the endocyclic oxygen or in case of derivatives of deoxynojirimycin, the nitrogen. We here focused on the hybridization aspect by straightforward derivatisation of the nitrogen of deoxynojirimycin to explore new structural motifs for glycosidase inhibition.
Novel guanidinium and urea derivatives of 1-deoxynojirimycin were prepared using a concise synthetic protocol and tested against a panel of glycosidases for their inhibitory properties. Particularly the guanidinium derivatives were surprisingly potent and selective [1]. The role of the R group was investigated and novel parent heterocycle structures were also explored.
[1] Kooij, R.; Branderhorst, H. M.; Bonte, S.; Wieclawska, S.; Martin, N. I.; Pieters, R. J. MedChemComm, 2013, 4, 387-393
