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Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions

Abstract : The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools to study various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluations of a series of mono-and polyfluorinated galactopyranosides is described. The preparation of all the monofluorogalactopyranosides, one trifluorinated galactopyranoside, and the tetrafluorinated galactopyranoside was achieved using a Chiron approach. The synthetic challenge they present combined with the scarcity of some of these compounds prompted us to evaluate their biological profile. Firstly, our fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells and compared with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, we used these carbohydrate probes as potential inhibitors for galactophilic lectins. We performed the first TROSY NMR, chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, we achieved the direct detection of the 19 F NMR resonance of the monofluorogalactopyranosides in presence and absence of LecA to monitor ligand binding. Lastly, these results were corroborated with the binding potency of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogs with fluorine atoms at C-3 and C-4 have weaker affinities with LecA as compared to compounds with fluorine atom at C-2 and C-6. This research focused on the chemical synthesis of "drug-like" low-molecular weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.
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Vincent Denavit, Danny Lainé, Chahrazed Bouzriba, Elena Shanina, Emilie Gillon, et al.. Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions. Chemistry - A European Journal, Wiley-VCH Verlag, 2019, 25 (17), pp.4478-4490. ⟨10.1002/chem.201806197⟩. ⟨hal-02104563⟩

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