Synthèse, évaluation biologique et caractérisation d'hexopyranoses fluorés

Un intérêt croissant est porté à la préparation de glucides polyfluorés. Le remplacement de fonctions hydroxyles par des atomes de fluor sur des squelettes d'hexoses pourrait permettre de découvrir de nouvelles molécules aux propriétés uniques. Les glycomimétiques fluorés sont des outils précieux pour l’étude de divers processus biochimiques. Dans nos activités de recherches visant à l’élaboration de nouvelles voies d’accès aux glucides fluorés, nous avons décrit la synthèse d’une série de galactopyranosides mono- et polyfluorés. Le défi synthétique que cela représente, associé à la rareté de certains de ces composés, nous a incités à évaluer leur profil biologique sur une protéine galactophile modèle, la PA-IL, qui est un facteur de virulence de Pseudomonas aeruginosa. Ces travaux de recherche ont porté sur la synthèse d'inhibiteurs d’intérêt pharmaceutique de faibles poids moléculaires qui contournent les inconvénients généralement associés aux oligosaccharides naturels. Seul un nombre limité de glucides fluorés ont été utilisés dans des études biologiques en raison de la difficulté inhérente à leur préparation. Cela nous a poussés à développer diverses voies de synthèse stéréosélectives de dérivés de sucres polyfluorés. Une grande diversité moléculaire a été obtenue grâce à une méthode de synthèse utilisant une approche Chiron à partir de lévoglucosan peu coûteux, processus qui est détaillé dans la présente thèse. Est décrite ici la préparation de composés fluorés dérivés d'hexopyranoses, de glycocluster, disaccharidiques, de glycopeptides et de glycoconjugué d'acide lipoïque. Des analyses structurales et des études RMN ont permis de confirmer la configuration et la conformation des molécules fluorées synthétisées. Certaines propriétés physico-chimiques comme la lipophilie ont été mesurées et l’influence de la stéréochimie relative des atomes de fluor contigus a pu être évaluée. Ces résultats mettent clairement en évidence les défis liés à la préparation de molécules organiques complexes polyhalogénées et ouvrent la voie à de nouveaux outils pertinents pour la chimie médicinale.There is a growing interest in the preparation of polyfluorinated carbohydrates. The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to the discovery of new chemical entities possessing unique properties. Fluorinated glycomimetics are invaluable tools to study various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, the synthesis of a series of mono- and polyfluorinated galactopyranosides is described. The synthetic challenge they present combined with the scarcity of some of these compounds prompted us to evaluate their biological profile on a model galactophilic protein, PA-IL, a virulence factor from Pseudomonas aeruginosa. This research focused on the chemical synthesis of “druglike” low-molecular weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides. A limited number of fluorinated carbohydrates have been used in biological investigations because of the challenge they present. This encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated sugars derivatives. Hence, we report the synthesis of various heavily fluorinated compounds using a Chiron approach from inexpensive levoglucosan. A rich molecular diversity has been achieved, and herein is described the preparation of heavily fluorinated hexopyranoses derivatives, glycocluster, disaccharides, glycopeptides and lipoic acid glycoconjugate. Structural analysis and NMR studies confirm the configuration and conformation for fluorinated carbohydrate analogs, and some physicochemical properties, such as lipophilicities, have been measured and corroborated with the relative stereochemistry of multi-vicinal fluorine atoms. These results clearly highlight challenges related to the preparation of polyhalogenated complex organic molecules and pave the way to access novel medically relevant tools

Stereoselective synthesis of fluorinated galactopyranosides as potential molecular probes for galactophilic proteins : assessment of monofluorogalactoside–LecA interactions

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono‐ and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation‐optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C‐3 and C‐4 showed weaker affinities with LecA as compared to those with the fluorine atom at C‐2 or C‐6. This research has focused on the chemical synthesis of “drug‐like” low‐molecular‐weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides