← Retour vers le trombinoscope
Professeur - Directeur Du LaboratoireMail :
Tel : 03 22 82 75 67
Fax : 03 22 82 75 60
Synthèse et fonctionnalisation d’oligosaccharides sulfatés
Nous obtenons des oligosaccharides anioniques, en particulier sulfatés, par différents voies : la synthèse chimique, la modification d’oligosaccharides naturels, et la dégradation contrôlée des polysaccharides. Nous développons les outils nécessaires à leur fractionnement, purification et l’analyse (HPAEC, ESI-MQS, MALDI).
Tensioactifs pour la flottation des métaux
La contamination des sols et des eaux par les métaux causant à la fois de graves problèmes d’environnement et de santé publique, il est nécessaire de traiter les zones contaminées. Parmi les nombreux procédés de dépollution existants, nous nous sommes intéressés à la flottation. Nous avons synthétisé tout un panel de tensioactifs à base de glucose, comportant une chaîne hydrocarbonée et une fonction complexante.
Ligands Multivalents
Nous avons développé une méthodologie de synthèse pour la fonctionnalisation de saccharides qui vont nous servir de charpente pour l’obtention des ligands multivalents. Cette méthodologie nous à permit d’obtenir un panel de charpentes oligosaccharidiques portant des azotures sur lesquelles nous avons ensuite « clické » des éléments de reconnaissance. Nous avons également étudié l’effet de la multivalence sur les inhibiteurs de glycosidases et obtenu des ligands multivalents de haute affinité pour les galectines.
Sulfated Galactan Derivative from Gracilaria fisheri Improves Histopathology and Alters Wound Healing-Related Proteins in the Skin of Excision Rats |
Comparative analysis of sulfated and sulfonated disaccharide analogs as TLR4 modulators and heparanase inhibitors |
Characterization of carboxylated cellulose nanofibrils and oligosaccharides from Kraft pulp fibers and their potential elicitor effect on the gene expression of Capsicum annuum |
Octanoyl esterification of low molecular weight sulfated galactan enhances the cellular uptake and collagen expression in fibroblast cells |
DP2, a Carbohydrate Derivative, Enhances In Vitro Osteoblast Mineralisation |
Sulfated Galactans from Gracilaria fisheri with Supplementation of Octanoyl Promote Wound Healing Activity In Vitro and In Vivo |
Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate |
Synthesis of novel S- and O-disaccharide analogs of heparan sulfate for heparanase inhibition |
Ring-Opening of Cyclodextrins: An Efficient Route to Pure Maltohexa-, Hepta-, and Octaoses |
Effects of CoCl2 on the regioselective tosylation of oligosaccharides |
One-Pot Synthesis of Asymmetrically Difunctionalized Oligomaltosides by Cyclodextrin Ring Opening |
Synthesis of new sulfated disaccharides for the modulation of TLR4-dependent inflammation |
A simple procedure to obtain a medium-size oligogalacturonic acids fraction from orange peel and apple pomace wastes |
Synthesis of defined oligohyaluronates-decorated liposomes and interaction with lung cancer cells |
Production of Oligosaccharides from Agrofood Wastes |
Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters built on Cyclodextrins Scaffolds |
Synthesis of multivalent S-glycosides analogs of a heparan sulfate sequence |
High resolution MALDI-TOF-MS and MS/MS: Application for the structural characterization of sulfated oligosaccharides |
Solid-phase synthesis of molecularly imprinted polymer nanolabels: Affinity tools for cellular bioimaging of glycans |
Biological impact of octyl D-glucopyranoside based surfactants |
Synthesis and Insecticidal Activities of Novel Solanidine Derivatives |
Kinetics of the incorporation of the main phenolic compounds into the lignan macromolecule during flaxseed development |
La chimie en Région Hauts-de-France : Chimie de la biomasse |
Applications of Glycosaminoglycans in the Medical, Veterinary, Pharmaceutical, and Cosmetic Fields |
Oligogalacturonic Acid Inhibits Vascular Calcification by Two Mechanisms: Inhibition of Vascular Smooth Muscle Cell Osteogenic Conversion and Interaction With Collagen |
Chirality inversion, supramolecular hydrogelation and lectin binding of two thiolactose amphiphiles constructed on a di-lauroyl-l-tartaric acid scaffold |
Glycochemical Applications of Diels-Alder Reaction |
Chapter 5 Recent Advances in the Synthesis of Sugar-based Surfactants |
Multivalent sialylation of β-thio-glycoclusters by Trypanosoma cruzi trans sialidase and analysis by high performance anion exchange chromatography |
Octyl glucoside derivatives: A tool against metal pollutants |
Cholesteryl and diosgenyl glycosteroids: synthesis and characterization of new smectic liquid crystals |
Development of an NMR metabolomics-based tool for selection of flaxseed varieties |
Chapter 11 Anionic oligosaccharides: synthesis and applications |
Synthesis of divalent ligands of β-thio-and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase |
Design and Synthesis of Hydrolytically Stable Multivalent Ligands Bearing Thiodigalactoside Analogues for Peanut Lectin and Human Galectin-3 Binding |
Background:
This article delves into the synthesis and biological evaluation of sulfated and sulfonated disaccharide analogs, exploring their interactions with toll-like receptor 4 (TLR4) and their potential as drug candidates for inflammatory diseases. A significant aspect of the study is the examination of these analogs as inhibitors of heparanase, an enzyme that cleaves glycosidic linkages in heparan sulfate, producing proinflammatory fragments that activate TLR4. The research presents a comparative analysis of sulfate and sulfonate groups in these compounds, evaluating their synthesis, biological activity, and specific roles in TLR4-mediated immune responses, with a particular focus on their ability to modulate heparanase activity. Compound 9 (6,6′-disulfonated disaccharide from methyl cellobioside) emerged as a potent TLR4 activator and a promising candidate for inflammatory drug development, exhibiting notable specificity and efficacy. The IC50 values for heparanase inhibition varied, highlighting distinct efficacy profiles for sulfonated and sulfated analogs, with cellobiose derivatives showing notable differences in inhibition capabilities.
Biomass-derived oligo- and polysaccharides may act as elicitors, i.e., bioactive molecules that trigger plant immune responses. This is particularly important to increase the resistance of plants to abiotic and biotic stresses. In this study, cellulose nanofibrils (CNF) gels were obtained by TEMPO-mediated oxidation of unbleached and bleached kraft pulps. The molecular structures were characterized with ESI and MALDI MS. Analysis of the fine sequences was achieved by MS and MS/MS of the water-soluble oligosaccharides obtained by acid hydrolysis of the CNF gels. The analysis revealed the presence of two families: one corresponding to homoglucuronic acid sequences and the other composed by alternating glucose and glucuronic acid units. The CNF gels, alone or with the addition of the water-soluble oligosaccharides, were tested on Chili pepper (Capsicum annuum). Based on the characterization of the gene expression with Next Generation Sequencing (NGS) of the C. annuum's total messenger RNA, the differences in growth of the C. annuum seeds correlated well with the downregulation of the pathways regulating photosynthesis. A downregulation of the response to abiotic factors was detected, suggesting that these gels would improve the resistance of the C. annuum plants to abiotic stress due to, e.g., water deprivation and cold temperatures.
Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is ubiquitously distributed throughout the animal kingdom and represents a key regulator of biological processes and a largely untapped reservoir of potential therapeutic targets. The temporal and spatial variations in the HS structure underpin the concept of “heparanome” and a complex network of HS binding proteins. However, despite its widespread biological roles, the determination of direct structure-to-function correlations is impaired by HS chemical heterogeneity. Attempts to correlate substitution patterns (mostly at the level of sulfation) with a given biological activity have been made. Nonetheless, these do not generally consider higher-level conformational effects at the carbohydrate level. Here, the use of NMR chemical shift analysis, NOEs, and spin–spin coupling constants sheds new light on how different sulfation patterns affect the polysaccharide backbone geometry. Furthermore, the substitution of native O-glycosidic linkages to hydrolytically more stable S-glycosidic forms leads to observable conformational changes in model saccharides, suggesting that alternative chemical spaces can be accessed and explored using such mimetics. Employing a series of systematically modified heparin oligosaccharides (as a proxy for HS) and chemically synthesized O- and S-glycoside analogues, the chemical space occupied by such compounds is explored and described.
Heparan sulfate (HS), a glycosaminoglycan related to heparin, is a linear polysaccharide, consisting of repeating disaccharide units. This compound is involved in multiple biological processes such as inflammation, coagulation, angiogenesis and viral infections. Our work focuses on the synthesis of simple HS analogs for the study of structure–activity relationships, with the aim of modulating these biological activities. Thioglycoside analogs, in which the interglycosidic oxygen is replaced by a sulfur atom, are very interesting compounds in terms of therapeutic applications. Indeed, the thioglycosidic bond leads to an improvement of their stability and can allow the inhibition of enzymes involved in physiological and pathological processes. In our previous work, we developed a synthetic sequence which led to a non-sulfated thiodisaccharide analog of HS. In this paper, we report our results of the development of a new synthetic method allowing access to the novel sulfated S-disaccharide, as well as to their oxygenated analogues (O-disaccharide and sulfated O-disaccharide). These 4 compounds were also tested for the inhibition of heparanase, an enzyme involved in biological processes like tumor growth and inflammation. The obtained IC50 values in the micromolar range showed the impact of the interglycosidic sulfur atom and the 6-sulfate group.
The tosyl functional group is commonly used in carbohydrate chemistry as a nucleofuge. Tosylation of the primary hydroxyls of carbohydrates are generally performed after orthogonal protection/deprotection reactions. However, it can be done regioselectively from unprotected sugars. Several examples have been described in the literature starting from free monosaccharides. Yields are generally good but may vary according to the nature of the sugar. Starting from free oligosaccharides, the regioselectivity and the yields generally drop significantly. The use of catalysts, such as DMAP or NEt3, improves the conversion but to the detriment of the regioselectivity. In our current work, we developed a tosylation reaction of the primary positions of several oligosaccharides with improved regioselectivity, using cobalt II chloride in catalytic amounts. Adaptability of this methodology has been tested on cellobiose, maltose, lactose, sucrose and maltotriose.
Natural sulfated glycans are key players in inflammation through TLR4 activation, and therefore synthetic exogenous sulfated saccharides can be used to downregulate inflammation processes. We have designed and synthesized new sulfated compounds based on small and biocompatible carbohydrates able to cross the BBB. Suitable protected donor and acceptor, obtained from a unique precursor, have been stereoselectively glycosylated to give an orthogonally protected cellobiose disaccharide. Selective deprotection and sulfation allowed to synthesize four differentially sulfated disaccharides, which have been characterized by NMR, HRMS and MS/MS. Together with their partially protected precursors, the new compounds were tested on HEF-TLR4 cells. Our results show the potential of small oligosaccharides to modulate TLR4 activity, confirming the need of sulfation and the key role of the 6-sulfate groups to trigger TLR4 signalization.
The homeostasis disruption of D-glucose causes diabetes, a dramatic world wide chronic disease. The type 1 diabetes is a succesfully treatable form, where the blood D-glucose is regulated by insulin treatement. In contrast the type 2 diabetes , the non Insulin dependent one, is problematic. The control of the D-glucose blood level via intestinal α-D-glucosidase inactivation can be achieved by using competitive inhibitors as iminosugars (e.g. acarbose) or sulfonium sugar derivatives (e.g. salacinol). Recently, an unprecedented result showed that multivalent diamond nanoparticules grafted with unmodified sugars displayed α-glucosidase inhibition at low micromolar concentrations. We describe herein the synthesis of multivalent glycoclusters using cyclodextrines (CDs) as scaffolds and their assessment as inhibithors of α-D-glucosidase. The glycoclusters were efficiently obtained from per-azido α, β and γ-CDs derivatives and propargyl glycosides using click-chemistry under microwave irradiation. The methodology was successfully applied to various protected and non-protected propargylated monosaccharides, including both O- and S- glycosides, giving clear evidences of its versatility. The targeted 6-per-glycosylated CDs were isolated in moderate to excellent yields (30-90 %) by silica gel chromatography. The results showed inhibition of α-glucosidase from Saccharomyces cerevisiae with IC50 values in a 32-132 µM range, lower than that of acarbose (IC50 ~250µM), a well knowm competitive inhibitor used in clinical treatment of type 2 diabetes. Preliminary experiments suggest a mixed-type non-competitive inhibition mode of these new glycoclusters.
Glycosaminoglycans (GAGs) are involved in the regulation of a large number of biological processes such as inflammation, cell signalling, angiogenesis, viral infection and coagulation. Unlike molecules isolated from tissues, pure molecules, derived from organic synthesis, can prevent side effects and are very useful tools for understanding the structure-activity relationships of many biological and pharmacological activities. In our research group, we focus particularly on the synthesis of multivalent thioglycoside analogs. In this article, we report the synthesis of new glycoclusters with thiodisaccharide units, S-analogs of heparan sulfate. The thiodisaccharide analog was obtained by nucleophilic displacement of a 4-triflate galactoside derivative, by an anomeric thiol of a glucuronic acid precursor. After modifying the aglycone part to introduce an azide, the thiodisaccharide was coupled to maltotriose scaffolds carrying one, two or three propargyl groups by CuAAC.
Development of many branches of industry has stimulated the search for new, effective surfactants with interesting properties. Potential use of alkyl glucose derivatives on a large scale, raises questions about the possible risks associated with their entry into the natural environment. To be able to evaluate this risk, the aim of the study was to determine the physicochemical properties of octyl D-glucopyranoside and its three derivatives: N-(octyl D-glucopyranosiduronyl)aspartic acid, N-(octyl D-glucopyranosiduronyl)glicyne and octyl D-glucopyranosiduronic acid. Moreover, their biodegradability by pure bacterial strains and biocenosis present in river water was examined. While descriptions of sugar-based surfactants on microbial cells are limited, the essential element of the study was to determine the effect of surfactants on cell surface properties of microorganisms isolated from activated sludge and compare it to the effects of the petroleum based surfactants and the surfactants produced from renewable materials. The results obtained indicate that physicochemical properties of surface active agents differ depending on the presence of functional groups in the surfactants molecules. What is more, the presence of amino acid substituent in the derivatives of octyl D-glucopyranoside resulted in a slight decrease in the surfactants biodegradation efficiency, in comparison to the compounds that did not contain such a substituent, prolonging this process from 5 to 10 days. Interestingly, even relatively slightly different derivatives modified the cell surface properties in a different way. Importantly, the surfactants based on octyl D-glucopyranoside have less negative impact on environmental microorganism and better biodegradability than the surfactant synthesized from petroleum products.
Cet article présente un tour d’horizon de quelques-unes des thématiques de recherche développées en région Hauts-de-France dans les domaines de la chimie de la biomasse.
Glycosaminoglycans (GAGs) are complex polysaccharides ubiquitously present in the extracellular matrix of mammalian tissues, where they constitute the gelatinous material responsible for maintaining the cells together, in an intimate association with a variety of proteins. Although their structures are not strictly regular, they are composed of a repeating unit of a hexosamine-containing disaccharide. Most of them possess uronic acid residues, and with the exception of hyaluronic acid, they also carry sulfate groups. As a consequence of their high negative charge, they have an extraordinary capacity to absorb water. GAGs participate in many relevant biological processes by interaction with a plethora of proteins, and thus, a large number of applications in different fields have been conceived for GAGs and their derivatives.
Herein we report the synthesis, characterization and self-assembly properties of two new thiolactose based amphiphiles constructed on a di-lauroyl-l-tartaric acid scaffold that only differ in the length of the spacer by an ethylene glycol unit. Upon dissolution in hot water the amphiphiles give rise to different colloidal systems at 25 [degree]C: the one with the shorter linker forms a supramolecular thermoreversible hydrogel at a concentration of 0.1 w/v% while the other renders a colloidal system at high dilution (0.005 w/v%). Dynamic Light Scattering, Electron Microscopy (TEM, SEM and E-SEM), fluorescence CMC determination, SAXS and Circular Dichroism experiments were used to characterize both systems. The experiments indicate that only the amphiphile carrying the shorter linker is able to form a crossed-linked network of micellar fibers and thus, a stable hydrogel is observed. The difference of an ethylene glycol unit in the spacer also causes the adoption of a different molecular assembly evidenced by the inversion of the self-assembled chiral arrangement. In addition, the amphiphiles were evaluated for their ability to bind to the PNA lectin using a turbidimetric method. Agglutination was observed in both cases, a process that was disrupted upon the addition of an excess of the disaccharide lactose.
Carbohydrates and their analogs are key molecules with a wide range of biological activities. These bioactive compounds are usually synthesized through derivatization of naturally occurring carbohydrates. Nevertheless, this strategy suffers from a limited range of naturally available monosaccharide building blocks and the necessity of laborious steps of protection and deprotection. Consequently new methods began to emerge and Diels-Alder reaction appeared to be a method of choice for their de novo production. The synthesis of carbohydrates and their analogs by means of cycloaddition reactions will be reviewed here. Moreover the potentiality of the use of monosaccharides to induce chirality in Diels-Alder reaction will be presented. Efficient methods for the synthesis of di- and tri-saccharides using the developments shown previously will be also introduced.
Derivatives of octyl glucoside modified by the introduction of a chemical function (carboxylic acid, hydroxamic acid) able to enhance the complexing properties of the surfactants toward metallic cations have been used as flotation collectors to remove various metallic cations from a water phase. Flotation experiments at the laboratory scale were performed on Fe(III), Cu(II), Cr(III), Cd(II), Zn(II), Ni(II) and As(III) aqueous solutions. The most interesting results were obtained in the extraction of Fe(III) and Cu(II). Interfacial properties were studied, and the effect of the polar head structure and anomeric configuration was analyzed. Structural variations have an influence on the efficiency and the foaming ability of these compounds. The introduction of a chelating functionality preserves the interfacial performances of these surfactants. Complexes equilibrium constants and species distribution diagrams for Fe(III) and the best flotation agents 2a and 2b were determined from multi-wavelength spectrophotometric pH titration. Both compounds showed analogous values for log β1, log β2 and log β3. The bidentanted Fe(III)-hydroxamate species (2:1 surfactant-metal ratio) reached a maximum concentration in the pH range of 5.5-6.5. At this pH, the best results in the flotation experiments were obtained for both compounds.
While present in large numbers in nature, studies on the physical chemical aspects of glycosteroids are quite rare and focused on cholesterol, and all compounds studied thus far have shown liquid crystalline properties in a narrow temperature range. New glycosteroids composed by cholesterol or diosgenin and different glycosidic moieties have been synthesized here in order to analyze the influence of the structure on the formation of mesophases. These compounds have been studied by crossed polarized optical microscopy. These studies have revealed that these new glycosteroids form Smetic A liquid crystals in a broad temperature range.
Herein, we describe the design and synthesis of a novel family of hydrolytically stable glycoclusters bearing thiodigalactoside (TDG) analogues as recognition elements of β-galactoside binding lectins. The TDG analogue was synthesized by thioglycosylation of a 6-S-acetyl-α-d-glucosyl bromide with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-β-d-galactose. Further propargylation of the TDG analogue allowed the coupling to azido-functionalized oligosaccharide scaffolds through copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) under microwave activation. The final mono-, di-, and tetravalent ligands were resistant to enzymatic hydrolisis by Escherichia coli β-galactosidase. Binding affinities to peanut agglutinin and human galectin-3 were measured by isothermal titration calorimetry which showed Ka constants in the micromolar range as well as a multivalent effect. Monovalent ligand exhibited a binding affinity higher than that of thiodigalactoside. Docking studies performed with a model ligand on both β-galactoside binding lectins showed additional interactions between the triazole ring and lectin amino acid residues, suggesting a positive effect of this aromatic residue on the biological activity.