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

Autor: Danny Lainé, Emilie Gillon, Chahrazed Bouzriba, Elena Shanina, Vincent Denavit, Denis Giguère, Christoph Rademacher, Sébastien Fortin, Anne Imberty
Přispěvatelé: Université Laval [Québec] (ULaval), Max Planck Institute of Colloids and Interfaces, Max-Planck-Gesellschaft, Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Image Science for Interventional Techniques (ISIT), Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS)-Clermont Université, Department of Biomolecular Systems [Potsdam], Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE11-0048,GLYCOMIME,Developement de glycomimétiques non glucidiques contre les lectines bactériennes(2017)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Chemistry-A European Journal
Chemistry-A European Journal, Wiley-VCH Verlag, 2019, 25 (17), pp.4478-4490. ⟨10.1002/chem.201806197⟩
Chemistry-A European Journal, 2019, 25 (17), pp.4478-4490. ⟨10.1002/chem.201806197⟩
ISSN: 0947-6539
1521-3765
Popis: 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 19 F 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.
Databáze: OpenAIRE
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