Pharmacological Chaperones by Design

One of the most successful approaches in the synthesis of inhibitors of t he g lycosidases i s t he s ubstitution of t he e ndocyclic ox ygen i n monosaccharides by a nitrogen atom to get iminosugars. Given that many diseases h ave t heir o rigin i n t he malfunctioning of t hese e nzymes, t his glycomimetics bear s trong p otential a s dr ug c andidates. A t th eir p rotonated state, iminosugars are s upposed to mimic the g lycosyloxacarbenium cat ion, a common intermediate in the enzymatic glycoside hydrolysis of both αand βglycosides. Similarly to this species, most of iminosugars lack an anomeric substituent a t t he pseudoanomeric carbon and behave as broad range g lycosidase inhibitors: they show configurational selectivity but not anomeric selectivity nor selectivity among isoenzymes. Fifteen years ago we conceived that the substitution of t he s p endocyclic n itrogen at om i n cl assical i minosugars b y a s p pseudoamide-type nitrogen should result in a very efficient overlapping of the orbital hosting the N-lone-pair with the antibonding σ* orbital of the contiguous C―O bond, increasing the anomeric effect. This orbital interaction leads to a very high stabilization of axially oriented pseudoanomeric substituents, resulting in compounds with configurational and conformational integrity even in polar solvents. We called this new type of glycomimetics sp-iminosugars. Most interestingly, th eir s ynthesis is compatible with molecular d iversity-oriented approaches, al lowing s tructural modifications at the heterocyclic co re, the hydroxylation profile and the nature and location of exocyclic substituents with a relatively lo w s ynthetic c ost. V ery s elective glycosidase l igands b ecame t hus accessible. By taken advantage of the information obtained from X-ray data of sp-iminosugar:glycosidase complexes, compounds capable of inducing the correct folding of lysosomal storage disorders (LSDs)-associated glycosidase mutants (pharmacological ch amperones) h ave b een d esigned. D ifferent s trategies for t he p reparation of t hese p harmacological ch aperones f or t he t reatment o f Gaucher disease, GM1 gangliosidosis and Fabry disease will be presented. 1. Jiménez Blanco, J. L.; Díaz Pérez, V. M.; Ortiz Mellet, C.; Fuentes, J.; García Fernández, J. M. Chem. Commun. 1997, 1969-1970. 2. Takai, T.; Higaki, K .; Aguilar-Moncayo, M .; Mena-Barragán, T. ; Hirano, Y. ; Yura, K .; Yu, L. ; Ninomiya, H.; García-Moreno, M. I. ; Sakakibara, Y.; Ohno, K.; Nanba, E.; Ortiz Mellet, C.; García Fernández, J. M.; Suzuki, Y. Mol. Ther. 2013, 21, 526-532. Proceedings IWBBIO 2014. Granada 7-9 April, 2014 389