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Méthodologies de synthèses pour la préparation de ‘puces à SAS’ : vers de nouveaux outils pour l’étude des interactions héparane sulfate /protéines

Abstract : Heparan sulfate (HS) is a linear polysaccharide found in animal tissues at the cell surface or in the extracellular matrix. HS chains display alternating highly negatively charged regions (S) and less charged ones (A). SAS domains with different topologies can thus be exposed at the cell surface with the aim of interacting specifically with different proteins. Gamma interferon (INF-γ) is a cytokine that binds tightly to HS chains. This interaction allows controlling numerous bioactivities of the cytokine (accumulation and location in tissues as well as blood clearance). The discovery of HS fragment able to modulate the activity of IFN-γ could open the way to new innovative therapeutics. To this aim we launched a program aiming at synthesizing mimetic of the SAS motifs found in HS. We devised a strategy allowing linking two synthetic S fragments of HS through a spacer. To this aim we selected two click chemistry reactions: the "CuAAC" triazole formation and "oxime ligation". To implement this strategy, we optimized, on a disaccharide model derived from cellobiose, a methodology allowing the functionalization of the reducing and non-reducing end of synthetic oligosaccharides by to orthogonal reactive functions. Then we extended the methodology to a HS tetrasaccharide fragment. In this work, we optimized two key reactions: an anomeric alkylation in water and a hydroxyl allylation in neutral condition
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Wenqing Liu. Méthodologies de synthèses pour la préparation de ‘puces à SAS’ : vers de nouveaux outils pour l’étude des interactions héparane sulfate /protéines. Chimie organique. Université Paris Sud - Paris XI, 2015. Français. ⟨NNT : 2015PA112006⟩. ⟨tel-02431586⟩

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