Synthesis of Glycomimetics and Gycodendrimers of Biological Interests

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Cell-surface glycoconjugates are responsible for a wide range of biological interactions at the origin of pathologies. Unfortunately, the nature of the binding interactions is weak and poorly selective. The following integrated research program is aimed at using conceptually novel strategies toward the design of high affinity and specificity carbohydrate dendritic nanomaterials for the targeting of conceptually innovative carriers against cancer, bacterial and viral infections. The concept of dendrimer design will be expanded to include two new features that have been overlooked so far. The conservative and restrictive approaches to dendrimer syntheses will be changed by using different chemical motifs between each layer, thus offering additional controls into the desired biophysical properties. This innovative "onion-peel" approach will provide much greater flexibility in the synthetic schemes leading to the novel dendrimer architectures. In addition, the above modifications will be improved by providing dendrimers harboring two different surface moieties to ensure the most efficient bacterial and cancer cell targeting. This will be particularly exemplified with two types of bacteria such as P. aeruginosa and uropathogenic E. coli involved in cystic fibrosis and pyelonephritis. To integrate bactericidal properties within the nanomaterials, we also proposed to simultaneously include antibacterial agents. As an additional level of improvement in the design of novel glycodendrimers, we also propose to use medicinal chemistry methodologies through which, much better ligands candidates will become accessible. Using the above two variables (multivalency and glycomimetic), more reliable, low valency analogs will be secured. A particular emphasis will be given to organometallic and asymmetric chemistry in order to provide access to structures with key chiral centers. Spacer length, distances, hydro/lipo-philicity will all be factors to be optimized. A novel aspect will also concentrate on the syntheses of a new family of self-assembled molecules calles glycodendrimersomes.