Molecules combining C60 and iminosugars: synthesis and multivalent effects on glycosidases inhibition – Sweet60s

1) preparation of the scaffolds
2) preparation of the iminosugars
3) preparation of the multivalent iminosugars
4) biological evaluation

The major synthetic problems have been solved for the preparation of the scaffolds as well as for the iminosugars.
Multivalent iminosugars of first generation have been prepared and their biological properties evaluated.

The different building blocks necessary for the preparation of the second generation multivalent inhibitors are available. The final synthetic steps are underway and the compounds will be available soon for biological investigations.

Cyclodextrin-based iminosugar click clusters: the first examples of multivalent pharmacological chaperones for the treatment of lysosomal storage disorder. C. Decroocq, D. Rodríguez-Lucena, K. Ikeda, N. Asano, P. Compain, ChemBioChem 2012, 13, 661-664.

Building liquid crystals from the 5-fold symmetrical pillar[5]arene core. I. Nierengarten, S. Guerra, M. Holler, J.-F. Nierengarten, R. Deschenaux, Chem. Commun. 2012, 48, 8072-8074.

The multivalent effect in glycosidase inhibition: probing the influence of valency, peripheral ligand structure and topology with cyclodextrin-based iminosugar click clusters. C. Decroocq, A. Joosten, R. Sergent, T. Mena Barragan, C. Ortiz Mellet, P. Compain, ChemBioChem 2013, 14, 2038-2049.

A mannosylated pillar[5]arene derivative: chiral information transfer and antiadhesive properties against uropathogenic bacteria. I. Nierengarten, K. Buffet, M. Holler, S. P. Vincent, J.-F. Nierengarten, Tetrahedron Lett. 2013, 54, 2398-2402.

A rigid macocyclic bis-malonate for the regioselective preparation of trans-1 and trans-3 fullerene bis-adducts. D. Sigwalt, M. Holler, J.-F. Nierengarten, Tetrahedron Lett. 2013, 54, 3160-3163.

Macrocyclic effects in the mesomorphic properties of liquid-crystalline pillar[5]- and pillar[6]arenes. I. Nierengarten, S. Guerra, M. Holler, L. Karmazin-Brelot, J. Barbera, R. Deschenaux, J.-F. Nierengarten, Eur. J. Org. Chem. 2013, 3675-3684.

Synthesis of optically pure [60]fullerene e,e,e-tris-adducts. S. Guerra, F. Schillinger, D. Sigwalt, M. Holler, J.-F. Nierengarten, Chem. Commun. 2013, 49, 4752-4754.

An expeditious regioselective synthesis of [60]fullerene e,e,e tris-adduct building blocks. D. Sigwalt, F. Schillinger, S. Guerra, M. Holler, M. Berville, J.-F. Nierengarten, Tetrahedron Lett. 2013, 54, 4241-4244.

The di-t-butylsilylene protecting group as a bridging unit in linear and macrocyclic bis-malonates for the regioselective multifunctionalization of C60. S. Guerra, T. M. N. Trinh, F. Schillinger, L. Muhlberger, D. Sigwalt, M. Holler, J.-F. Nierengarten, Tetrahedron Lett. 2013, 54, 6251-6257.

Rescue of functional CFTR channels in cystic fibrosis: a dramatic multivalent effect using iminosugar clusters-based correctors. P. Compain, C. Decroocq, A. Joosten, J. De Sousa, D. Rodríguez-Lucena, T. D. Butters, J. Bertrand, R. Clément, C. Boinot, F. Becq, C. Norez, ChemBioChem 2013, 14, 2050-2058.

Fullerene-sp2-iminosugar balls as multimodal ligands for lectins and glycosidases: a mechanistic hypothesis for the inhibitory multivalent effect. R. Risquez-Cuadro, J. M. Garcia Fernandez, J.-F. Nierengarten, C. Ortiz Mellet, Chem. Eur. J. 2013, 19, 16791-16803.

Polycationic pillar[5]arene derivatives: interaction with DNA and biological applications. I. Nierengarten, M. Nothisen, D. Sigwalt, T. Biellmann, M. Holler, J.-S. Remy, J.-F. Nierengarten, Chem. Eur. J. 2013, 19, 17552-17558.

A systematic investigation of iminosugar click clusters as pharmacological chaperones for the treatment of gaucher disease. A. Joosten, C. Decroocq, J. De Sousa, J. Schneider, E. Etame, T. D. Butters, P. Compain, ChemBioChem 2014, 15, 309-319.

A convergent strategy for the synthesis of second-generation iminosugar clusters using clickable trivalent dendrons. A. Joosten, J. P. Schneider, M. L. Lepage, C. Tarnus, A. Bodlenner, P. Compain, Eur. J. Org. Chem. 2014, 1866-1872. (Spotlights in Angew. Chem. Int. Ed. 2014, 53, 2272)

Iminosugar-based glycopolypeptides: glycosidase inhibition with bioinspired glycoprotein analogue micellar self-assemblies. C. Bonduelle, J. Huang, T. Mena-Barragán, C. Ortiz Mellet, C. Decroocq, E. Etamé, A. Heise, P. Compain, S. Lecommandoux, Chem. Commun. 2014, 50, 3350-3352.

Glucocerebrosidase enhancers for selected Gaucher disease genotypes by modification of ?-1-C-substituted imino-D-xylitols (DIXs) by click chemistry. J. Serra-Vinardell, L. Díaz, J. Casas, D. Grinberg, L. Vilageliu, H. Michelakakis, I. Mavridou, J.M.F.G. Aerts, C. Decroocq, P. Compain, A. Delgado, ChemMedChem 2014, 9, 1744-1754.

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores. M. L. Lepage, A. Meli, A. Bodlenner, C. Tarnus, F. De Riccardis, I. Izzo, P. Compain, Beilstein J. Org. Chem. 2014, 10, 1406-1412 (invited paper for a special issue entitled “Multivalent glycosystems for nanoscience”)

A fullerene hexakis-adduct decorated with 12 iminosugar residues has been synthesized and systematically evaluated towards various glycosidases. Remarkably, this dodecavalent derivative displays a binding enhancement of up to 3 orders of magnitude over the corresponding monovalent ligand. This example represents the first evidence for a significant multivalent effect in the field of glycosidase inhibition. The Sweet60s project is based on this promising preliminary finding with the aim of rationalizing the significant inhibition enhancements observed for glycosidases with multivalent fullerene-based iminosugars. A better understanding of the multivalent effect for enzyme inhibition in general and the establishment of structure/property relationships for multivalent iminosugar-fullerene inhibitors in particular are of fundamental importance for a rational design of tailored multivalent molecules with desirable biological properties. In a second step, we will evaluate the potential of the multivalent approach towards therapeutic applications. Specifically, our objective is to apply for the first time the concept of multivalency to the field of pharmacological chaperones for the treatment of lysosomal diseases with the aim of improving significantly their enhancing activity.