A decade of glycodendrimer chemistry

The last decade of glycodendrimers research has witnessed tremendous sophistication in both their design and in their biological applications. Some of these artificial multiantennary glycans have reached animal testing and preliminary results are very encouraging, particularly those involving bacterial antiadhesins and antibody neutralization as observed with the Galili antigen implicated in xenotransplantation. Key scaffolding structures have become commercially available on large scale and several dendrimers were shown to be none toxic in cell and animal assays. These beautiful architectures have permitted to shed new lights on multivalent carbohydrate protein interactions. In fact, their potent ability to cross-link multivalent or aggregated protein receptors is helping redefine the classical glycoside cluster effect. The multivalent effect will be reexamined with a recent case involving cyanovirin, a high affinity oligomannose binding protein from Nostoc ellipsosporum. Advantages of glycodendrimers, in comparison to glycopolymers, will then be briefly discussed followed by the detailed description on synthetic strategies and common scaffolds used for their preparation. Structural glycodendrimer drawbacks will be described and solutions brought to solve problems associated with their steric hindrance, and thus lack of sugar accessibility at higher generation, will be presented. Both most common chemical ligations and chemoenzymatic synthesis will be outlined. Finally, the synthesis of "smart" glycodendrimers and glycoclusters' newer generation involving rapid covalent assembly of sugars by transition metal catalyzed cross-coupling reactions using palladium and cobalt will be described. The state of the art preparation of glycodendrimers library by dynamic combinatorial chemistry (adaptive chemistry) and self-assembly around various transition metals is now opening the field to an even higher level of creativity. These novel strategies are of particular interest given the fact that several protein receptors (ex. galectins) are actually contemplating the binding of the same carbohydrate ligands which they can although select on the basis of the valency and three dimensional topology.