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Synthèse par chimie click non métallo-catalysée de glycoconjugués macromoléculaires d'interêt médical

Abstract : The aim of the project is to develop new anomeric modification of oligosaccharides for the synthesis of glycoconjugates by metal-free click chemistry. Synthetic glycans have shown a great potential in medical and nanotechnology related fields. The current use of metallic catalyst during synthesis and the risk of contamination of the final product represent a drawback which could restrain their applications. Therefore an efficient metal free synthesis of glycoconjugates could be of great interest to circumvent this obstacle.Two distinct synthetic strategies have been explored for the metal free coupling of complex oligosaccharides on polymers to yield block-copolymers and glycoadsorbants. The glycopolymers were synthetized by a Michael addition between a thiol functionalized oligosaccharide and a maleimide or bromo-maleimide functionalized polymer. The nanoparticles obtained from the self-assembly of theses amphiphilic copolymers in water were characterized. The polycaprolactone-b-xylooligosaccharides copolymers presenting a reducible linkage were self-assembled into nanoparticles and assessed as model for the delivery of hydrophobic drugs. This system showed a selective release of the entrapped molecules in reducing environment making it an interesting system for the intra-tumoral delivery of anti-cancer drugs. Glycoadsorbents were prepared by a Diels Alder reaction between a solid matrix displaying a maleimide moiety and furyl functionalized oligosaccharides. The affinity matrixes obtained allowed the selective purification of lectins. The blood group antigen (A;B) grafted matrixes displayed good properties for the trapping of corresponding anti-A or anti-B antibodies. These types of immunoadsorbants have great potential for the treatment of immune diseases like the Guillain-Barré syndrome.To conclude, two efficient anomeric modification and coupling strategies of oligosaccharides have been developed, opening the way to the metal free synthesis of various glycoconjugates.
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Antoine Petrelli. Synthèse par chimie click non métallo-catalysée de glycoconjugués macromoléculaires d'interêt médical. Chimie organique. Université Grenoble Alpes, 2015. Français. ⟨NNT : 2015GREAV043⟩. ⟨tel-01687493⟩

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