Laboratoire des Glucides UMR CNRS 6219
Université de Picardie Jules Verne 10 rue Baudelocque 80039 Amiens Cedex
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1. Amphiphilic CD and self-assembly properties

The team has developped for few years skills in modified cyclodextrin synthesis and particularly, amphiphilic cyclodextrins by grafting DMPE with 6-amino-6-deoxy-permethylated b-CD [8,11]. The interactions of these molecules with membranes were studied by X rays scattering,  Newton black films,  2H  and 31P NMR, and detergent properties against mimetic membrane of DMP [5,6]. Black films structure indicated a compact assembling of lipidic chains with strong interactions between CDs and also water molecules. Moreover, a first experience showed that CDs were able to cross a Bloob Brain Barrier in vitro model (collaboration with Université d’Artois) without toxicity. Potential applications of these molecules seem to be very promising. Unfortunately, the synthesis of such compounds is time consuming and difficult, the DMPE is expensive and easily degradable so the synthesis to large scale for in vivo tests is impossible.It’s why, for 5 yours, we have developped new access to amphiphilic cyclodextrins by chemistry [3,7]  and enzymatic catalysis [4,9,14,15].


2. Oligosaccharide-cyclodextrin conjugates: synthesis and biological affinity towards lectin Con A


Ten glycosylated cyclodextrins were synthesized by 20 steps pathway and were fully characterized. These molecules were used to study the structure-activity relationship between n-glycans and gp120 glycoprotein of VIH and macrophage receptors. Saccharide moieties  were designed to perfectly mimic “high mannose” structure of N-glycans. Firstly, the synthesis of glycosylated cyclodextrins bearing pentasaccharides or saccharidic moieties of higher dp, needed the development of a rapid and efficient synthesis of mimics of N-glycans with “high mannose” structures. [1,2]

In a second step, the coupling of the cyclodextrin was realized by peptidic linkage using a CD functionnalized with spacer arm bearing carboxylic acid. Affinity studies have been performed with the series of synthesized compounds and the lectin, Concanavalin A. These indicate that the tri-dimensional structure of these cyclodextrin-appended oligosaccharides plays a key role in the studied molecular recognition event. Moreover we report here an example of switchable and tunable ligand for Con A based on b-CD-oligosaccharide conjugate that can shift between two conformational states by virtue of a judiciously located self-inclusion element.







3. Development and formulation of oral and sublingual solutions of midazolam containing cyclodextrins

In absence of dedicated children formulation, intravenous solutions of midazolam (MDZ), which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of MDZ anesthesia premedications, we have already prepared a 0.2% (W/v) aqueous solution for oral administration containing g-CD 12. The use of g-CD offered two advantages: the masking of the solution bitterness and the enhancement of MDZ solubility. However in aqueous solution, acido-basic equilibrium involves that MDZ exists under two forms: a closed and pharmacologically active form and an open-form. In this study, the objective is to enhance the MDZ bioavailability by increasing the closed-form/open-form ratio using methylated CDs, which are reported to be more suitable for sublingual formulation. The overall results demonstrated that RAMEB increases both solubility and closed-form/open-form ratio of MDZ in aqueous acidic solution, making the development of novel sublingual formulation possible.

4. Catalyse supramoléculaire en milieu hétérogène.

In aqueous organometallic catalysis, properties of catalytic species are greatly influenced by the nature of the hydrosoluble ligands which are used to solubilise the metal in water. Particularly, bidentate ligands are known to undergo a better stabilization of organometallic complexes than monodentates ones. Moreover, the chelation of this kind of ligands is able to generate original selectivities in catalyzed reactions1. Unfortunately, the synthesis of hydrosoluble bidentate ligands is often difficult. The elaboration of self-assembled bidentate ligand by supramolecular interactions between a cyclodextrin dimer and monophosphanes was investigated. The main advantage of this strategy is to lead to the elaboration of a library of bidentate ligands from a small number of building blocks.