Publications by authors named "Sebastien Vidal"

84 Publications

30  TW and 33  fs pulses delivered by a Ti:Sa amplifier system seeded with a frequency-doubled fiber laser.

Appl Opt 2020 Aug;59(24):7390-7395

We report a full experimental comparison study on the injection of a Ti:Sa multi-terawatt amplifier chain with a standard 15 fs Ti:Sa oscillator and 35 fs frequency-doubled fiber oscillator. The study highlights that the Ti:Sa oscillator, with high performance in terms of pulse duration and spectral width, can be replaced by the frequency-doubled fiber oscillator to seed Ti:Sa amplifier chains almost without any compromise on the output pulse duration and picosecond contrast. Finally, we demonstrate for the first time to our knowledge a 30 TW and 33 fs Ti:Sa amplifier injected by a fiber oscillator.
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http://dx.doi.org/10.1364/AO.401351DOI Listing
August 2020

Supramolecular Assembly of TPE-Based Glycoclusters with Dicyanomethylene-4H-pyran (DM) Fluorescent Probes Improve Their Properties for Peroxynitrite Sensing and Cell Imaging.

Chemistry 2020 Nov 6;26(63):14445-14452. Epub 2020 Oct 6.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Université de Lyon, 1, Rue Victor Grignard, 69622, Villeurbanne, France.

Two red-emitting dicyanomethylene-4H-pyran (DM) based fluorescent probes were designed and used for peroxynitrite (ONOO ) detection. Nevertheless, the aggregation-caused quenching effect diminished the fluorescence and restricted their further applications. To overcome this problem, tetraphenylethylene (TPE) based glycoclusters were used to self-assemble with these DM probes to obtain supramolecular water-soluble glyco-dots. This self-assembly strategy enhanced the fluorescence intensity, leading to an enhanced selectivity and activity of the resulting glyco-dot comparing to DM probes alone in PBS buffer. The glyco-dots also exhibited better results during fluorescence sensing of intracellular ONOO than the probes alone, thereby offering scope for the development of other similar supramolecular glyco-systems for chemical biological studies.
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http://dx.doi.org/10.1002/chem.202002772DOI Listing
November 2020

Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors.

Bioorg Chem 2020 05 2;98:103713. Epub 2020 Mar 2.

University of Monastir, Faculty of Sciences of Monastir, Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Avenue of the Environment, 5019 Monastir, Tunisia; Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address:

A series of novel isoxazolidines based on benzaldehyde derivatives have been synthesized from the cycloaddition of chiral menthone-based nitrone and allyl phenyl ethers. All synthetic compounds were assessed for their in vitro PPA, HPA and HLAG inhibitory activity. The results revealed that all targets exhibited better inhibitory effect against PPA (12.3 ± 0.4 < IC < 38.2 ± 0.9 μM), HPA (10.1 ± 0.4 < IC < 26.8 ± 0.2 μM) and HLAG (65.4 ± 1.2 < IC < 274.8 ± 1.1 μM) when compared with the reference inhibitor, acarbose (IC = 284.6 ± 0.3 μM for PPA, 296.6 ± 0.8 μM for HPA, 780.4 ± 0.3 μM for HLAG) with the highest PPA inhibitory activity was ascribed to compound 3g against both PPA and HPA, and 3b against HLAG enzymes, respectively. Structural activity relationships (SARs) were also established for all synthesized compounds and the interaction modes of the most potent inhibitors (3g for PPA and HPA, 3b for HLAG) and the active site with residues of three enzymes were confirmed through molecular docking studies. Furthermore, a combination of molecular docking analysis with the in vitro activities can help to improve prediction success and encourages the uses of some of these molecules as potential alternatives toward the modulation of T2D.
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http://dx.doi.org/10.1016/j.bioorg.2020.103713DOI Listing
May 2020

Safety First: A Recent Case of a Dichloromethane Injection Injury.

Authors:
Sébastien Vidal

ACS Cent Sci 2020 Feb;6(2):83-86

Université Claude Bernard Lyon 1 and CNRS, Gif-sur-Yvette 91198, France.

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http://dx.doi.org/10.1021/acscentsci.0c00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047271PMC
February 2020

Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition.

Org Biomol Chem 2020 02 10;18(5):931-940. Epub 2020 Jan 10.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (K = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg and ∼43% at 60 mg kg. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.
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http://dx.doi.org/10.1039/c9ob01190kDOI Listing
February 2020

Fluorescent glycoconjugates and their applications.

Chem Soc Rev 2020 Jan 9;49(2):593-641. Epub 2020 Jan 9.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246, CNRS and Université Claude Bernard Lyon 1, Université de Lyon, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.

Glycoconjugates and their applications as lectin ligands in biology have been thoroughly investigated in the past decades. Meanwhile, the intrinsic properties of such multivalent molecules were limited essentially to their ability to bind to their receptors with high selectivity and/or avidity. The present review will focus on multivalent glycoconjugates displaying an additional capability such as fluorescence properties not only for applications toward imaging of cancer cells and detection of proteins or pathogens but also for drug delivery systems toward targeted cancer therapy. This review is a collection of research articles discussed in the context of the structural features of fluorescent glycoconjugates organized according to their fluorescent core scaffold and with their representative applications.
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http://dx.doi.org/10.1039/c8cs00118aDOI Listing
January 2020

Lectin PLL3, a Novel Monomeric Member of the Seven-Bladed β-Propeller Lectin Family.

Molecules 2019 Dec 11;24(24). Epub 2019 Dec 11.

Department of Biochemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic.

The species is a Gram-negative bacteria of the family that is known for its mutualistic relationship with nematodes and pathogenicity toward insects. This study is focused on the characterization of the recombinant lectin PLL3 with an origin in subsp. . PLL3 belongs to the PLL family of lectins with a seven-bladed β-propeller fold. The binding properties of PLL3 were tested by hemagglutination assay, glycan array, isothermal titration calorimetry, and surface plasmon resonance, and its structure was determined by X-ray crystallography. Obtained data revealed that PLL3 binds similar carbohydrates to those that the other PLL family members bind, with some differences in the binding properties. PLL3 exhibited the highest affinity toward l-fucose and its derivatives but was also able to interact with -methylated glycans and other ligands. Unlike the other members of this family, PLL3 was discovered to be a monomer, which might correspond to a weaker avidity effect compared to homologous lectins. Based on the similarity to the related lectins and their proposed biological function, PLL3 might accompany them during the interaction of with both the nematode partner and the insect host.
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http://dx.doi.org/10.3390/molecules24244540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943638PMC
December 2019

Thiophenol detection using an AIE fluorescent probe through self-assembly with TPE-based glycoclusters.

Org Biomol Chem 2019 10;17(41):9251-9256

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246, CNRS and Université Claude Bernard Lyon 1, Université de Lyon, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.

We describe a novel green-emitting tetraphenylethylene-dicyanomethylene-4H-pyran (TPE-DCM) based fluorescent probe (TD-1). Conjugating TPE and DCM moieties allowed TD-1 to display high selectivity for thiophenol with excellent AIE properties in aqueous solution. Nevertheless, the poor water solubility of the hydrophobic structure resulted in a weak and unstable emission intensity. The non-covalent self-assembly of TD-1 with a TPE glycocluster (TPE2S) led to a largely improved water solubility producing a reliable and stable sensing system. The corresponding glyco-probe could sensitively detect exogenous thiophenol concentrations in PBS buffer or environmental water samples.
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http://dx.doi.org/10.1039/c9ob01937eDOI Listing
October 2019

Deciphering multivalent glycocluster-lectin interactions through AFM characterization of the self-assembled nanostructures.

Soft Matter 2019 Sep;15(36):7211-7218

Université de Lyon, Ecole Centrale de Lyon, Institut des Nanotechnologies de Lyon INL UMR-5270 CNRS, 36 avenue Guy de Collongue, 69134 Ecully, France.

Pseudomonas aeruginosa is a human opportunistic pathogen responsible for lung infections in cystic fibrosis patients. The emergence of resistant strains and its ability to form a biofilm seem to give a selective advantage to the bacterium and thus new therapeutic approaches are needed. To infect the lung, the bacterium uses several virulence factors, like LecA lectins. These proteins are involved in bacterial adhesion due to their specific interaction with carbohydrates of the host epithelial cells. The tetrameric LecA lectin specifically binds galactose residues. A new therapeutic approach is based on the development of highly affine synthetic glycoclusters able to selectively link with LecA to interfere with the natural carbohydrate-LecA interaction. In this study, we combined atomic force microscopy imaging and molecular dynamics simulations to visualize and understand the arrangements formed by LecA and five different glycoclusters. Our glycoclusters are small scaffolds characterized by a core and four branches, which terminate in a galactose residue. Depending on the nature of the core and the branches, the glycocluster-lectin interaction can be modulated and the affinity increased. We show that glycocluster-LecA arrangements highly depend on the glycocluster architecture: the core influences the rigidity of the geometry and the directionality of the branches, whereas the nature of the branch determines the compactness of the structure and the ease of binding.
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http://dx.doi.org/10.1039/c9sm00371aDOI Listing
September 2019

Tetraphenylethylene-based glycoclusters with aggregation-induced emission (AIE) properties as high-affinity ligands of bacterial lectins.

Org Biomol Chem 2018 11;16(45):8804-8809

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie UMR 5246, CNRS - Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.

Tetraphenylethylene (TPE) is fluorescent through aggregation induced emission (AIE) in water. Herein, TPE was used as the core of glycoclusters that target the bacterial lectins LecA and LecB of Pseudomonas aeruginosa. Synthesis of these TPE-based glycoclusters was accomplished by using azide-alkyne "click" chemistry. The AIE properties of the resulting glycoclusters could be readily verified, but imaging could not be pursued due to the overlap of the fluorescence signals from cells and bacteria. Nonetheless, the glycoclusters displayed nanomolar affinities toward LecA and LecB. Further evaluation in a cell-based anti-adhesive assay highlighted a limited decrease in adhesion (20%) for the fucosylated glycocluster. This confirmed that these TPE-based glycoclusters are indeed LecA and LecB high-affinity ligands. Nevertheless, the hypotheses involving their application in imaging or anti-adhesive therapy could not be verified.
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http://dx.doi.org/10.1039/c8ob02035cDOI Listing
November 2018

The anti-adhesive effect of glycoclusters on Pseudomonas aeruginosa bacteria adhesion to epithelial cells studied by AFM single cell force spectroscopy.

Nanoscale 2018 Jul;10(26):12771-12778

Université de Lyon, Ecole Centrale de Lyon, Institut des Nanotechnologies de Lyon INL UMR-5270, CNRS, 36 avenue Guy de Collongue, 69134 Ecully, France.

The human opportunistic pathogen Pseudomonas aeruginosa (PA) is responsible for chronic infections of the respiratory epithelium in cystic fibrosis patients. PA takes advantage of an arsenal of virulence factors to infect and colonize human lungs. Among them, the lectin LecA favours epithelium invasion by interacting with host cell globotriaosylceramide (Gb3). A new therapeutic approach is based on the development of synthetic multivalent molecules (glycoclusters) targeting LecA with a higher affinity than its natural ligand. Atomic force microscopy-single cell force spectroscopy has been used to study the effect of glycoclusters on the bacteria-cell interaction. Glycoclusters have been shown to affect the detachment work and detachment force of the bacteria-cell interaction. The specificity and the efficiency of the glycocluster in targeting the lectin and destabilizing the PA-epithelial cell adhesion are demonstrated and discussed.
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http://dx.doi.org/10.1039/c8nr03285hDOI Listing
July 2018

Fixing the Conformation of Calix[4]arenes: When Are Three Carbons Not Enough?

Chemistry 2018 Mar 26;24(17):4436-4444. Epub 2018 Feb 26.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CO2-Glyco, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622, Villeurbanne, France.

Calix[4]arenes are unique macrocycles that through judicious functionalisation at the lower rim can be either fixed in one of four conformations or remain conformationally flexible. Introduction of propynyl or propenyl groups unexpectedly provides a new possibility; a unidirectional conformational switch, with the 1,3-alternate and 1,2-alternate conformers switching to the partial cone conformation, whilst the cone conformation is unchanged, under standard experimental conditions. Using H NMR kinetic studies, rates of switching have been shown to be dependent on the starting conformation, upper-rim substituent, where reduction in bulk enables faster switching, solvent and temperature with 1,2-alternate conformations switching fastest. Ab initio calculations (DFT) confirmed the relative stabilities of the conformations and point towards the partial cone conformer being the most stable of the four. The potential impact on synthesis through the "click" reaction has been investigated and found not to be significant.
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http://dx.doi.org/10.1002/chem.201705955DOI Listing
March 2018

Perylenediimide-based glycoclusters as high affinity ligands of bacterial lectins: synthesis, binding studies and anti-adhesive properties.

Org Biomol Chem 2017 Dec;15(47):10037-10043

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie UMR 5246, CNRS - Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.

The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with K values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core.
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http://dx.doi.org/10.1039/c7ob02749dDOI Listing
December 2017

Supramolecular assembly of fluorogenic glyco-dots from perylenediimide-based glycoclusters for targeted imaging of cancer cells.

Chem Commun (Camb) 2017 Oct;53(87):11937-11940

Key Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Rd., Shanghai 200237, P. R. China.

Supramolecular self-assembly between perylenediimide-based glycoclusters and a red-emitting fluorophore produces structurally uniform and stable glyco-dots amenable to targeted fluorogenic imaging of liver and triple-negative breast cancer cells.
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http://dx.doi.org/10.1039/c7cc07666eDOI Listing
October 2017

Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of β-1,4-Galactosyltransferase 7 (β4GalT7).

Chemistry 2017 Dec 27;23(71):18057-18065. Epub 2017 Nov 27.

Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00, Lund, Sweden.

Xyloside analogues with substitution of the endocyclic oxygen atom by sulfur or carbon were investigated as substrates for β-1,4-galactosyltransferase 7 (β4GalT7), a key enzyme in the biosynthesis of glycosaminoglycan chains. The analogues with an endocyclic sulfur atom proved to be excellent substrates for β4GalT7, and were galactosylated approximately fifteen times more efficiently than the corresponding xyloside. The 5a-carba-β-xylopyranoside in the d-configuration proved to be a good substrate for β4GalT7, whereas the enantiomer in the l-configuration showed no activity. Further investigations by X-ray crystallography, NMR spectroscopy, and molecular modeling provided a rationale for the pronounced activity of the sulfur analogues. Favorable π-π interactions between the 2-naphthyl moiety and a tyrosine side chain of the enzyme were observed for the thio analogues, which open up for the design of efficient GAG primers and inhibitors.
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http://dx.doi.org/10.1002/chem.201704267DOI Listing
December 2017

Design and Synthesis of Galactosylated Bifurcated Ligands with Nanomolar Affinity for Lectin LecA from Pseudomonas aeruginosa.

Chembiochem 2017 06 27;18(11):1036-1047. Epub 2017 Apr 27.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université Montpellier, ENSCM, Place Eugène Bataillon, CC1704, 34095, Montpellier cedex 5, France.

Lectin A (LecA) from Pseudomonas aeruginosa is an established virulence factor. Glycoclusters that target LecA and are able to compete with human glycoconjugates present on epithelial cells are promising candidates to treat P. aeruginosa infection. A family of 32 glycodendrimers of generation 0 and 1 based on a bifurcated bis-galactoside motif have been designed to interact with LecA. The influences both of the central multivalent core and of the aglycon of these glycodendrimers on their affinity toward LecA have been evaluated by use of a microarray technique, both qualitatively for rapid screening of the binding properties and also quantitatively (K ). This has led to high-affinity LecA ligands with K values in the low nanomolar range (K =22 nm for the best one).
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http://dx.doi.org/10.1002/cbic.201700154DOI Listing
June 2017

C-Glycopyranosyl Arenes and Hetarenes: Synthetic Methods and Bioactivity Focused on Antidiabetic Potential.

Chem Rev 2017 02 25;117(3):1687-1764. Epub 2017 Jan 25.

Department of Organic Chemistry, University of Debrecen , P.O. Box 400, Debrecen H-4002, Hungary.

This Review summarizes close to 500 primary publications and surveys published since 2000 about the syntheses and diverse bioactivities of C-glycopyranosyl (het)arenes. A classification of the preparative routes to these synthetic targets according to methodologies and compound categories is provided. Several of these compounds, regardless of their natural or synthetic origin, display antidiabetic properties due to enzyme inhibition (glycogen phosphorylase, protein tyrosine phosphatase 1B) or by inhibiting renal sodium-dependent glucose cotransporter 2 (SGLT2). The latter class of synthetic inhibitors, very recently approved as antihyperglycemic drugs, opens new perspectives in the pharmacological treatment of type 2 diabetes. Various compounds with the C-glycopyranosyl (het)arene motif were subjected to biological studies displaying among others antioxidant, antiviral, antibiotic, antiadhesive, cytotoxic, and glycoenzyme inhibitory effects.
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http://dx.doi.org/10.1021/acs.chemrev.6b00475DOI Listing
February 2017

Crystal structure of 2-isopropyl-5,7'-dimethyl-1',3',3a',6',8a',8b'-hexa-hydro-spiro-[cyclo-hexane-1,6'-furo[3,4-d]imidazo[1,5-b]isoxazol]-8'(7'H)-one.

Acta Crystallogr E Crystallogr Commun 2016 Aug 19;72(Pt 8):1150-2. Epub 2016 Jul 19.

University of Monastir, Heterocyclic Chemistry Laboratory, Products, Natural and Reactivity, Faculty of Sciences of Monastir, Avenue of the Environment, 5000 Monastir, Tunisia.

In the title compound, C17H28N2O3, the isoxazolidine ring adopts an envelope conformation with the O atom deviating from the mean plane of the other four ring atoms by 0.617 (1) Å. In the crystal, mol-ecules are linked via weak C-H⋯O hydrogen bonds, forming chains which extend along the b-axis direction.
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http://dx.doi.org/10.1107/S2056989016010641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971860PMC
August 2016

Toward the Rational Design of Galactosylated Glycoclusters That Target Pseudomonas aeruginosa Lectin A (LecA): Influence of Linker Arms That Lead to Low-Nanomolar Multivalent Ligands.

Chemistry 2016 Aug 14;22(33):11785-94. Epub 2016 Jul 14.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie UMR 5246, CNRS - Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622, Villeurbanne, France.

Anti-infectious strategies against pathogen infections can be achieved through antiadhesive strategies by using multivalent ligands of bacterial virulence factors. LecA and LecB are lectins of Pseudomonas aeruginosa implicated in biofilm formation. A series of 27 LecA-targeting glycoclusters have been synthesized. Nine aromatic galactose aglycons were investigated with three different linker arms that connect the central mannopyranoside core. A low-nanomolar (Kd =19 nm, microarray) ligand with a tyrosine-based linker arm could be identified in a structure-activity relationship study. Molecular modeling of the glycoclusters bound to the lectin tetramer was also used to rationalize the binding properties observed.
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http://dx.doi.org/10.1002/chem.201602047DOI Listing
August 2016

Genomic Rearrangements and Functional Diversification of lecA and lecB Lectin-Coding Regions Impacting the Efficacy of Glycomimetics Directed against Pseudomonas aeruginosa.

Front Microbiol 2016 31;7:811. Epub 2016 May 31.

Equipes de Recherche, Bactéries Pathogènes Opportunistes et Environnement, Centre de Ressources Biologiques - Environnement Microbiologie Lyon, UMR Centre National de la Recherche Scientifique 5557 Ecologie Microbienne, Université Lyon 1 and VetAgro Sup Lyon, France.

LecA and LecB tetrameric lectins take part in oligosaccharide-mediated adhesion-processes of Pseudomonas aeruginosa. Glycomimetics have been designed to block these interactions. The great versatility of P. aeruginosa suggests that the range of application of these glycomimetics could be restricted to genotypes with particular lectin types. The likelihood of having genomic and genetic changes impacting LecA and LecB interactions with glycomimetics such as galactosylated and fucosylated calix[4]arene was investigated over a collection of strains from the main clades of P. aeruginosa. Lectin types were defined, and their ligand specificities were inferred. These analyses showed a loss of lecA among the PA7 clade. Genomic changes impacting lec loci were thus assessed using strains of this clade, and by making comparisons with the PAO1 genome. The lecA regions were found challenged by phage attacks and PAGI-2 (genomic island) integrations. A prophage was linked to the loss of lecA. The lecB regions were found less impacted by such rearrangements but greater lecB than lecA genetic divergences were recorded. Sixteen combinations of LecA and LecB types were observed. Amino acid variations were mapped on PAO1 crystal structures. Most significant changes were observed on LecBPA7, and found close to the fucose binding site. Glycan array analyses were performed with purified LecBPA7. LecBPA7 was found less specific for fucosylated oligosaccharides than LecBPAO1, with a preference for H type 2 rather than type 1, and Lewis(a) rather than Lewis(x). Comparison of the crystal structures of LecBPA7 and LecBPAO1 in complex with Lewis(a) showed these changes in specificity to have resulted from a modification of the water network between the lectin, galactose and GlcNAc residues. Incidence of these modifications on the interactions with calix[4]arene glycomimetics at the cell level was investigated. An aggregation test was used to establish the efficacy of these ligands. Great variations in the responses were observed. Glycomimetics directed against LecB yielded the highest numbers of aggregates for strains from all clades. The use of a PAO1ΔlecB strain confirmed a role of LecB in this aggregation phenotype. Fucosylated calix[4]arene showed the greatest potential for a use in the prevention of P. aeruginosa infections.
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http://dx.doi.org/10.3389/fmicb.2016.00811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885879PMC
June 2016

Crystal structure of 5-chloro-methyl-N-methyl-4-[(4-phenyl-1,2,3-triazol-1-yl)meth-yl]isoxazolidine-3-carboxamide.

Acta Crystallogr E Crystallogr Commun 2016 Mar 20;72(Pt 3):378-81. Epub 2016 Feb 20.

Université de Monastir, Laboratoire de Synthèse Hétérocyclique, Produits Naturels et Réactivités, Faculté des Sciences de Monastir, Avenue de l'Environnement, 5000 Monastir, Tunisia.

The title compound, C15H18ClN5O2, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In both mol-ecules, the isoxazolidine rings have an envelope conformation with the O atoms at the flap positions. Each mol-ecule has three stereogenic centres with configurations 2(S), 3(S) and 4(R), confirmed by resonant scattering. Their conformations are significantly different, for example in mol-ecule A the phenyl ring is inclined to the triazole ring by 32.5 (2)°, while in mol-ecule B the corresponding dihedral angle is 10.7 (2)°. In the crystal, the A and B mol-ecules are linked via an N-H⋯O and a C-H⋯O hydrogen bond. These units are linked by C-H⋯O and C-H⋯N hydrogen bonds, forming slabs parallel to the ab plane. There are C-H⋯π inter-actions present within the slabs.
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http://dx.doi.org/10.1107/S2056989016002784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778830PMC
March 2016

Pentavalent pillar[5]arene-based glycoclusters and their multivalent binding to pathogenic bacterial lectins.

Org Biomol Chem 2016 Apr 14;14(13):3476-81. Epub 2016 Mar 14.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CO2-Glyco, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Université de Lyon, 43 Boulevard du 11 Novembre 1918, F-6922 Villeurbanne, France.

Anti-adhesive glycoclusters offer potential as therapeutic alternatives to classical antibiotics in treating infections. Pillar[5]arenes functionalised with either five galactose or five fucose residues were readily prepared using CuAAC reactions and evaluated for their binding to three therapeutically relevant bacterial lectins: LecA and Lec B from Pseudomonas aeuruginosa and BambL from Burkholderia ambifaria. Steric interactions were demonstrated to be a key factor in achieving good binding to LecA with more flexible galactose glycoclusters showing enhanced activity. In contrast binding to the fucose-selective lectins confirmed the importance of topology of the glycoclusters for activity with the pillar[5]arene ligand proving a selective ligand for BambL.
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http://dx.doi.org/10.1039/c6ob00220jDOI Listing
April 2016

Pillar[5]arene-Based Glycoclusters: Synthesis and Multivalent Binding to Pathogenic Bacterial Lectins.

Chemistry 2016 Feb 4;22(9):2955-63. Epub 2016 Feb 4.

Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087, Strasbourg Cedex 2, France.

The synthesis of pillar[5]arene-based glycoclusters has been readily achieved by CuAAC conjugations of azido- and alkyne-functionalized precursors. The lectin binding properties of the resulting glycosylated multivalent ligands have been studied by at least two complementary techniques to provide a good understanding. Three lectins were selected from bacterial pathogens based on their potential therapeutic applications as anti-adhesives, namely LecA and LecB from Pseudomonas aeruginosa and BambL from Burkholderia ambifaria. As a general trend, multivalency improved the binding to lectins and a higher affinity can be obtained by increasing to a certain limit the length of the spacer arm between the carbohydrate subunits and the central macrocyclic core.
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http://dx.doi.org/10.1002/chem.201504921DOI Listing
February 2016

Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition.

Eur J Med Chem 2016 Jan 10;108:444-454. Epub 2015 Dec 10.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 - Glycochimie, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France. Electronic address:

Glycogen phosphorylase (GP) is a target for the treatment of hyperglycaemia in the context of type 2 diabetes. This enzyme is responsible for the depolymerization of glycogen into glucose thereby affecting the levels of glucose in the blood stream. Twelve new d-glucopyranosylidene-spiro-isoxazolines have been prepared from O-peracylated exo-D-glucals by regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides generated in situ by treatment of the corresponding oximes with bleach. This mild and direct procedure appeared to be applicable to a broad range of substrates. The corresponding O-unprotected spiro-isoxazolines were evaluated as glycogen phosphorylase (GP) inhibitors and exhibited IC50 values ranging from 1 to 800 μM. Selected inhibitors were further evaluated in vitro using rat and human hepatocytes and exhibited significant inhibitory properties in the primary cell culture. Interestingly, when tested with human hepatocytes, the tetra-O-acetylated spiro-isoxazoline bearing a 2-naphthyl residue showed a much lower IC50 value (2.5 μM), compared to that of the O-unprotected analog (19.95 μM). The most promising compounds were investigated in Zucker fa/fa rat model in acute and sub-chronic assays and decreased hepatic glucose production, which is known to be elevated in type 2 diabetes. This indicates that glucose-based spiro-isoxazolines can be considered as anti-hyperglycemic agents in the context of type 2 diabetes.
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http://dx.doi.org/10.1016/j.ejmech.2015.12.004DOI Listing
January 2016

Glycofullerenes: Sweet fullerenes vanquish viruses.

Authors:
Sébastien Vidal

Nat Chem 2016 Jan;8(1):4-6

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (UMR 5246), Université Claude Bernard Lyon 1 and CNRS, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.

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http://dx.doi.org/10.1038/nchem.2422DOI Listing
January 2016

Glycogen phosphorylase inhibitors: a patent review (2013 - 2015).

Expert Opin Ther Pat 2016 11;26(2):199-212. Epub 2016 Jan 11.

a Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246 , CNRS and Université Claude Bernard Lyon 1 , Villeurbanne , France.

Introduction: Control of glycemia is crucial in the treatment of type 2 diabetes complications. Glycogen phosphorylase (GP) releases glucose from the liver into the blood stream. Design of potent GP inhibitors is a therapeutic strategy in the context of type 2 diabetes.

Areas Covered: Glucose-based inhibitors have found potential applications since they now reach low nanomolar Ki values. Another set of patents disclose cholic acid/7-aza-indole conjugates for targeted drug delivery to the liver. A series of benzazepinones have also been reported as potent GP inhibitors. In vitro data are reported for GP inhibition but the in vivo biological data at the cellular or animal levels are often missing, even though the literature reported for these molecules is also discussed.

Expert Opinion: A structural analogy between glucose-based GP inhibitors and C-glucosides targeting sodium glucose co-transporter 2 (SGLT2) is intriguing. Cholic acid/7-aza-indole conjugates are promising in vivo drug delivery systems to the liver. Benzazepinones were very recently described and no associated literature is available, making it very difficult to comment at present. While industry has slowed down on GP inhibitors design, academic groups are pursuing investigations and have provided potential drug candidates which will resuscitate the interest for GP, including its potential for targeting cancer.
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http://dx.doi.org/10.1517/13543776.2016.1131268DOI Listing
September 2016

Design of Glycosyltransferase Inhibitors: Serine Analogues as Pyrophosphate Surrogates?

Chempluschem 2015 Oct 14;80(10):1525-1532. Epub 2015 Jul 14.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2-Glycochimie, UMR 5246, CNRS and Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622, Villeurbanne, France.

Mimicking the diphosphate moiety of nucleotide diphosphate sugars with serine analogues provided modest glycosyltransferase inhibitors. The synthetic strategy employed a combination of glycosylation, amide bond formation and azide-alkyne "click" chemistry. Inhibition constants (K ) in the high micromolar range were obtained with a selection of five galactosyltransferases. Cocrystals of three inhibitors bound at the active site of a blood group A/B synthesizing glycosyltransferase were analysed. The structures and inhibitory patterns of the analogues demonstrate the flexibility of the enzymes which complicates the rational design of glycosyltransferase inhibitors.
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http://dx.doi.org/10.1002/cplu.201500282DOI Listing
October 2015

Importance of topology for glycocluster binding to Pseudomonas aeruginosa and Burkholderia ambifaria bacterial lectins.

Org Biomol Chem 2015 Dec 28;13(46):11244-54. Epub 2015 Sep 28.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM, place Eugène Bataillon, CC1704, 34095 Montpellier Cedex 5, France.

Pseudomonas aeruginosa (PA) and Burkholderia ambifaria (BA) are two opportunistic Gram negative bacteria and major infectious agents involved in lung infection of cystic fibrosis patients. Both bacteria can develop resistance to conventional antibiotherapies. An alternative strategy consists of targeting virulence factors in particular lectins with high affinity ligands such as multivalent glycoclusters. LecA (PA-IL) and LecB (PA-IIL) are two tetravalent lectins from PA that recognise galactose and fucose respectively. BambL lectin from BA is trimeric with 2 binding sites per monomer and is also specific for fucose. These three lectins are potential therapeutic targets in an anti-adhesive anti-bacterial approach. Herein, we report the synthesis of 18 oligonucleotide pentofuranose-centered or mannitol-centered glycoclusters leading to tri-, penta- or decavalent clusters with different topologies. The linker arm length between the core and the carbohydrate epitope was also varied leading to 9 galactoclusters targeting LecA and 9 fucoclusters targeting both LecB and BambL. Their dissociation constants (Kd) were determined using a DNA-based carbohydrate microarray technology. The trivalent xylo-centered galactocluster and the ribo-centered fucocluster exhibited the best affinity for LecA and LecB respectively while the mannitol-centered decafucocluster displayed the best affinity to BambL. These data demonstrated that the topology and nature of linkers were the predominant factors for achieving high affinity rather than valency.
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http://dx.doi.org/10.1039/c5ob01445jDOI Listing
December 2015

Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa.

Org Biomol Chem 2015 Aug;13(31):8433-44

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM, place Eugène Bataillon, CC1704, 34095 Montpellier Cedex 5, France.

Pseudomonas aeruginosa (PA) is a major public health care issue due to its ability to develop antibiotic resistance mainly through adhesion and biofilm formation. Therefore, targeting the bacterial molecular arsenal involved in its adhesion and the formation of its biofilm appears as a promising tool against this pathogen. The galactose-binding LecA (or PA-IL) has been described as one of the PA virulence factors involved in these processes. Herein, the affinity of three tetravalent mannose-centered galactoclusters toward LecA was evaluated with five different bioanalytical methods: HIA, ELLA, SPR, ITC and DNA-based glycoarray. Inhibitory potential towards biofilms was then assessed for the two glycoclusters with highest affinity towards LecA (Kd values of 157 and 194 nM from ITC measurements). An inhibition of biofilm formation of 40% was found for these galactoclusters at 10 μM concentration. Applications of these macromolecules in anti-bacterial therapy are therefore possible through an anti-adhesive strategy.
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http://dx.doi.org/10.1039/c5ob00948kDOI Listing
August 2015

3-Glucosylated 5-amino-1,2,4-oxadiazoles: synthesis and evaluation as glycogen phosphorylase inhibitors.

Beilstein J Org Chem 2015 17;11:499-503. Epub 2015 Apr 17.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (UMR 5246), Laboratoire de Chimie Organique 2, Université Claude Bernard Lyon 1 and CNRS; 43 Boulevard du 11 Novembre 1918, F-69622, Villeurbanne, France.

Glycogen phosporylase (GP) is a promising target for the control of glycaemia. The design of inhibitors binding at the catalytic site has been accomplished through various families of glucose-based derivatives such as oxadiazoles. Further elaboration of the oxadiazole aromatic aglycon moiety is now reported with 3-glucosyl-5-amino-1,2,4-oxadiazoles synthesized by condensation of a C-glucosyl amidoxime with N,N'-dialkylcarbodiimides or Vilsmeier salts. The 5-amino group introduced on the oxadiazole scaffold was expected to provide better inhibition of GP through potential additional interactions with the enzyme's catalytic site; however, no inhibition was observed at 625 µM.
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http://dx.doi.org/10.3762/bjoc.11.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419504PMC
May 2015