Synthèse de nouveaux dérivés de l'acide b-hydroxyaspartique b-Substitués (inhibiteurs du transport du glutamate dans le Système Nerveux Central (SNC))

Nos travaux ont porté sur la mise au point de synthèse de nouveaux dérivés b-substitués b-hydroxy aspartates : Inhibiteurs du transport du glutamate dans le système nerveux centrale (SNC). Ces analogues d'aspartates ont été caractérisés par différentes méthodes spectroscopiques (RMN-1H, RMN-13C et HRMS) et leur pureté énantiomérique a été confirmée par analyses HPLC chirale et des mesures de pouvoir rotatoire. Ce manuscrit est organisé en trois chapitres : la première partie présente un point bibliographique sur le système glutamatergique dans le SNC, en rappelant les différents récepteurs et transporteurs du glutamate dans ce système ainsi leurs agonistes et antagonistes spécifiques.Puis, nous avons décrit un aperçu sur les différentes synthèses de dérivés aspartates b-substitués et leurs activités inhibitrices vers les transporteurs du Glu dans le SNC.Afin d'avoir une grande diversité dans la structure les dérivés b-substitués b-hydroxy aspartates et réduire le temps de préparation et le nombre d'étapes de synthèse, nous avons développé dans la troisième partie de ce manuscrit deux stratégies originales et récentes pour préparer des dérivés -substitués -hydroxy aspartates via une aminohydroxylation asymétrique de Sharpless, qui est considérée comme l'étape clé dans cette synthèse.Enfin, Les résultats préliminaires de tests biologiques sur les dérivés b-substitués b-hydroxy aspartates protégés montrent que ces composés ne présentent aucune toxicité vers les cellules nerveuses de l'hippocampe de rat. L'étude de la cytotoxicité et l'activité inhibitrice de dérivés b-substitués b-hydroxy aspartates totalement déprotégés vis à vis du transport du glutamate dans le SNC sont actuellement en cours.Our work focused on the development of synthesis of originals b-substituted b-hydroxy aspartates derivatives: Inhibitors of glutamate transport in the central nervous system (CNS).These analogs of aspartate have been characterized by various spectroscopic methods (1H-NMR, 13C-NMR and HRMS) and their enantiomeric purity was confirmed by chiral HPLC analysis and D measurement.This manuscript is organized into three chapters: the first part presents a bibliographical point of the glutamatergic system in CNS, recalling the different receptors and glutamate transporters in this system and their specific agonists and antagonists.Then, we described an overview of the various syntheses of b-substituted aspartates derivatives and their inhibitory activities toward glutamate transporters in CNS.In order, to have a great diversity in the structure of b-substituted b-hydroxy aspartates derivatives and reduce preparation time and the number of synthetic steps, we have developed in the third part of this manuscript two recent and original strategies for prepare b-substituted b-hydroxy aspartates derivatives via asymmetric aminohydroxylation Sharpless, who is considered the key step in this synthesis. Finally, preliminary results of biological tests on optically pure aspartates derivatives showed no toxicity to nerve cells of the rat hippocampus. The study of the inhibitory activity of these derivatives towards transport of glutamate in CNS is currently underway.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Concomitant polymorphism in the stereoselective of a ß-benzyl-ß-hydroxyaspartate analogue

International audienceTwo concomitant polymorphs, (I) and (II), of a -benzyl- -hydroxyaspartate analogue [systematic name: dibenzyl 2-benzyl-2-hydroxy-3-(4-methylphenylsulfonamido)succinate], C32H31NO7S, crystallize from a mixture of ethyl acetate and cyclohexane at ambient temperature. The structure of (I) has triclinic (P1) symmetry and that of (II) monoclinic (P21/c) symmetry. Both crystal structures are made up of a stacking of homochiral racemic dimers (2S,3S and 2R,3R) which are internally connected by a similar R2 2(9) hydrogen-bonding pattern consisting of intermolecular N--H O andO--H O hydrogen bonds. The centroid of the racemic dimer lies on an inversion centre. The main structural difference between the two polymorphs is the conformational orientation of two of the four aromatic rings present in the molecule. Polymorph (II) is found to be twinned by reticular merohedry with twin index 3 and twin fractions 0.854 (1) and 0.146 (1)

Diastereospecific synthesis of new 4-substituted L-theanine derivatives.

International audienceConsidering the biological activity of L-theanine as a potent agonist of NMDA receptors, impacting on glutamatergic synapse activity, we have developed an asymmetric synthesis of new enantiomerically pure 4-substituted L-theanine derivatives. The key step is a stereospecific alkylation on a previously synthesized and correctly protected (S)-pyroglutamate

Solvent- and catalyst-free transamidations of unprotected glycosyl carboxamides

International audienceThe transamidation reactions of unprotected mono- and disaccharidic carboxamides with various primary and secondary arylic, heterocyclic or aliphatic amines are described. This new method is green and atom efficient and gives good to high yields. Notably, the conditions do not require either a solvent or a catalyst and give ammonia as a single by-product. The described coupling reaction is compatible with a variety of functional groups and was used in the synthesis of various glycosidic derivatives and biologically relevant glycolipids. A plausible reaction mechanism involving an intermolecular H-bond activation of the starting carboxamides is proposed

A focus on the asymmetric synthesis of a novel threo-ß-benzyl-ß-hydroxy aspartate analogue

International audienceConsidering the biological activity of b-alkyl-b-hydroxyaspartate derivatives as potent blockers of glutamate transporters (EAATs) impacting on glutamatergic synapses activity, we have developed a concise, asymmetric synthesis of enantiomerically pure threo-b-benzyl-b-hydroxyaspartates. The key step is a regiospecific and stereoselective Sharpless asymmetric aminohydroxylation (SAA) on previously synthesized benzyl fumarate

Al-Rich Ordered Mesoporous Silica SBA-15 Materials: Synthesis, Surface Characterization and Acid Properties

International audienceAl-SBA-15 is an interesting mesoporous material having highly ordered nanopores and a large surface area, which is widely employed as catalysts and adsorbents, but relatively few studies on the surfaces properties of this type of materials have been carried out. The purpose of the present work was to advance knowledge on the textural properties of Al-SBA-15 by applying the accurate NLDFT method as well as to gain insight into the surface characterisation and acidic trend of this material. Mesoporous Al-SBA-15 molecular sieves, in three SiO2/Al2O3 ratios: 50, 75 and 100 were accomplished by post-synthesis alumination in aqueous solution of a purely siliceous SBA-15 material. The obtained solids were characterized using powder X-ray diffraction (XRD), X-ray fluorescence (XRF), N-2 adsorption-desorption (BET/DFT), transmission electron microscopy (TEM), water adsorption and zeta potential measurements. The results indicate that Al atoms have been successfully incorporated into the framework of the hexagonal mesoporous SBA-15. The aluminum introduced amount has remarkably affected the surface properties of the SBA-15 solid, indeed microporosity decreased. Furthermore, the esterification test showed that the Al-SBA-15 material exhibit Bronsted acid properties with an interesting activity leading to yields of similar to 90% of biodiesel

Characterization of l -Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N -Methyl- d -aspartate Receptor Modulators Based on Its Backbone

International audienceL-Theanine (or L-γ-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of L-theanine and L-γ-N-propyl-Gln and their corresponding D-isomers. L-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-D-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons. This activity was retained on NMDA receptors expressed in Xenopus oocytes. In addition, both GluN2A and GluN2B containing NMDA receptors were equally modulated by L-theanine. The stereochemical change from L-theanine to D-theanine along with the substitution of the ethyl for a propyl moiety in the γ-N position of Land D-theanine significantly enhanced the biological efficacy, as measured on cultured hippocampal neurons. L-Theanine structure thus represents an interesting backbone to develop novel NMDA receptor modulators