Laboratoire de Glycochimie, des Antimicrobiens
et des Agroressources UMR 7378 CNRS


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Axe de recherche : Chimie pour le Développement Durable

Description des travaux de recherche

Synthèse et substitution sélective d'oligosaccharides : Les oligosaccharides sont des  acteurs de la reconnaissance cellulaire. D'une part, nous étudions l'impact sur différentes activités biologiques de modifications chimiques de fragments de pectines. D'autre part, nous tentons d'identifier les oligosaccharides de type héparane sulfate responsables de la reconnaissance d'un virus pour sa cellule cible. 
Molécules marquées au 13C : Certains lignanes du lin montrant des activités biologiques intéressantes. Les molécules doublement marquées que nous synthétisons permettent l'étude de leur métabolisme par RMN. 
Molécules amphiphiles : un des axes de recherche de notre équipe est dédié à la synthèse d'agents de flottation capables de complexer les métaux lourds, utilisables en dépollution 

Mots clés : N.C.

Sélection de publications

Biological impact of octyl D-glucopyranoside based surfactants
Zdarta, A.; Pacholak, A.; Smułek, W.; Zgoła-Grześkowiak, A.; Ferlin, N.; Bil, A.; Kovensky, J.; Grand, E.; Kaczorek, E.
Chemosphere 2018.
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.

Synthesis and Insecticidal Activities of Novel Solanidine Derivatives
Beaulieu, R.; Grand, E.; Stasik, I.; Attoumbre, J.; Chesnais, Q.; Gobert, V.; Ameline, A.; Giordanengo, P.; Kovensky, J.
Pest Manag Sci 2018, 0.
Potato (Solanum tuberosum) is the fourth culture in the world and is widely used in the agri-food industries. They generate by-products where alpha-chaconine and alpha-solanine, the two major solanidine based glycoalkaloids of potato, are present. As secondary metabolites, they play an important role in the protecting system of potato and are involved in plant protection against insects. To add value to these by-products, we described herein new glycoalkaloids that could have phytosanitary properties. RESULTS: Solanidine, as a renewable source, was modified with an azido linker and coupled by Copper catalyzed alkyne azide cycloaddition (CuAAC) to alkynyl derivatives of the monosaccharides found in the natural potato glycoalkakoids: D-glucose, D-galactose and L-rhamnose. The efficacy of our compounds was evaluated on the potato aphid Macrosiphum euphorbiae. The synthetic compounds have stronger aphicidal properties against nymphs than unmodified solanidine. They also showed strong aphicidal activities on adults and a negative impact on fecundity. CONCLUSION: Our synthetic neoglycoalkaloids affected Macrosiphum euphorbiae survival at the nymphal stage as well as at the adult stage. Furthermore, they induced a decrease of fecundity. Our results show that chemical modifications of by-products may afford new sustainable compounds for crop and plant protection. This article is protected by copyright. All rights reserved.

Kinetics of the incorporation of the main phenolic compounds into the lignan macromolecule during flaxseed development
Ramsay, A.; Fliniaux, O.; Quero, A.; Molinie, R.; Demailly, H.; Hano, C.; Paetz, C.; Roscher, A.; Grand, E.; Kovensky, J.; Schneider, B.; Mesnard, F.
Food Chem. 2017, 217, 1-8.
The main flax lignan, secoisolariciresinol diglucoside, is stored in a macromolecule containing other ester-bound phenolic compounds. In this study, NMR and HPLC-UV analyses were performed on flaxseeds harvested at different developmental stages to identify and quantify the main phenolic compounds produced during seed development. Extraction was carried out with or without alkaline hydrolysis to determine if these molecules accumulate in the lignan macromolecule and/or in a free form. Monolignol glucosides accumulate in a free form up to 9.85mg/g dry matter at the early developmental stages. Hydroxycinnamic acid glucosides and flavonoid accumulate (up to 3.18 and 4.07mg/g dry matter, respectively) in the later developmental stages and are ester-bound in the lignan macromolecule. Secosiolariciresinol diglucoside accumulates (up to 28.65mg/g dry matter) in the later developmental stages in both forms, mainly ester-bound in the lignan macromolecule and slightly in a free form.

Phenylpropanoid profiling reveals a class of hydroxycinnamoyl glucaric acid conjugates in Isatis tinctoria leaves
Nguyen, T. K.; Jamali, A.; Grand, E.; Morreel, K.; Marcelo, P.; Gontier, E.; Dauwe, R.
Phytochemistry 2017, 144, 127-140.
The brassicaceous herb, Isatis tinctoria, is an ancient medicinal plant whose rosette leaf extracts have anti-inflammatory and anti-allergic activity. Brassicaceae are known to accumulate a variety of phenylpropanoids in their rosette leaves acting as antioxidants and a UV-B shield, and these compounds often have pharmacological potential. Nevertheless, knowledge about the phenylpropanoid content of I. tinctoria leaves remains limited to the characterization of a number of flavonoids. In this research, we profiled the methanol extracts of I. tinctoria fresh leaf extracts by liquid chromatography - mass spectrometry (LC-MS) and focused on the phenylpropanoid derivatives. We report the structural characterization of 99 compounds including 18 flavonoids, 21 mono- or oligolignols, 2 benzenoids, and a wide spectrum of 58 hydroxycinnamic acid esters. Besides the sinapate esters of malate, glucose and gentiobiose, which are typical of brassicaceous plants, these conjugates comprised a large variety of glucaric acid esters that have not previously been reported in plants. Feeding with (13)C6-glucaric acid showed that glucaric acid is an acyl acceptor of an as yet unknown acyltransferase activity in I. tinctoria rosette leaves. The large amount of hydroxycinnamic acid derivatives changes radically our view of the woad metabolite profile and potentially contributes to the pharmacological activity of I. tinctoria leaf extracts.

Measurement of cytotoxicity and irritancy potential of sugar-based surfactants on skin-related 3D models
Lu, B.; Miao, Y.; Vigneron, P.; Chagnault, V.; Grand, E.; Wadouachi, A.; Postel, D.; Pezron, I.; Egles, C.; Vayssade, M.
Toxicol. in Vitro 2017, 40, 305-312.
Sugar-based surfactants present surface-active properties and relatively low cytotoxicity. They are often considered as safe alternatives to currently used surfactants in cosmetic industries. In this study, four sugar-based surfactants, each with an eight carbon alkyl chain bound to a glucose or a maltose headgroup through an amide linkage, were synthesized and compared to two standard surfactants. The cytotoxic and irritant effects of surfactants were evaluated using two biologically relevant models: 3D dermal model (mouse fibroblasts embedded in collagen gel) and reconstituted human epidermis (RHE, multi-layered human keratinocytes). Results show that three synthesized surfactants possess lower cytotoxicity compared to standard surfactants as demonstrated in the 3D dermal model. Moreover, the IC50s of surfactants against the 3D dermal model are higher than IC50s obtained with the 2D dermal model (monolayer mouse fibroblasts). Both synthesized and standard surfactants show no irritant effects after 48h of topical application on RHE. Throughout the study, we demonstrate the difficulty to link the physico-chemical properties of surfactants and their cytotoxicity in complex models. More importantly, our data suggest that, prior to in vivo tests, a complete understanding of surfactant cytotoxicity or irritancy potential requires a combination of cellular and tissue models.

Applications of Glycosaminoglycans in the Medical, Veterinary, Pharmaceutical, and Cosmetic Fields
Kovensky, J.; Grand, E.; Uhrig, M. L.
Industrial Applications of Renewable Biomass Products: Past, Present and Future 2017, 135-164.
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.

Physico-chemical properties and cytotoxic effects of sugar-based surfactants: Impact of structural variations
Lu, B.; Vayssade, M.; Miao, Y.; Chagnault, V.; Grand, E.; Wadouachi, A.; Postel, D.; Drelich, A.; Egles, C.; Pezron, I.
Colloids Surf B Biointerfaces 2016, 145, 79-86.
Surfactants derived from the biorefinery process can present interesting surface-active properties, low cytotoxicity, high biocompatibility and biodegradability. They are therefore considered as potential sustainable substitutes to currently used petroleum-based surfactants. To better understand and anticipate their performances, structure-property relationships need to be carefully investigated. For this reason, we applied a multidisciplinary approach to systematically explore the effect of subtle structural variations on both physico-chemical properties and biological effects. Four sugar-based surfactants, each with an eight carbon alkyl chain bound to a glucose or maltose head group by an amide linkage, were synthesized and evaluated together along with two commercially available standard surfactants. Physico-chemical properties including solubility, Krafft point, surface-tension lowering and critical micellar concentration (CMC) in water and biological medium were explored. Cytotoxicity evaluation by measuring proliferation index and metabolic activity against dermal fibroblasts showed that all surfactants studied may induce cell death at low concentrations (below their CMC). Results revealed significant differences in both physico-chemical properties and cytotoxic effects depending on molecule structural features, such as the position of the linkage on the sugar head-group, or the orientation of the amide linkage. Furthermore, the cytotoxic response increased with the reduction of surfactant CMC. This study underscores the relevance of a methodical and multidisciplinary approach that enables the consideration of surfactant solution properties when applied to biological materials. Overall, our results will contribute to a better understanding of the concomitant impact of surfactant structure at physico-chemical and biological levels.

Chapter 5 Recent Advances in the Synthesis of Sugar-based Surfactants
Kovensky, J.; Grand, E.
Biomass Sugars for Non-Fuel Applications 2016, 159-204.

Octyl glucoside derivatives: A tool against metal pollutants
Ferlin, N.; Grassi, D.; Ojeda, C.; Castro, M. J. L.; Cirelli, A. F.; Kovensky, J.; Grand, E.
Colloids and Surfaces A: Physicochemical and Engineering Aspects 2015, 480, 439-448.
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.

Cholesteryl and diosgenyl glycosteroids: synthesis and characterization of new smectic liquid crystals
Beaulieu, R.; Gottis, S.; Meyer, C.; Grand, E.; Deveaux, V.; Kovensky, J.; Stasik, I.
Carbohydr. Res. 2015, 404, 70-78.
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.

Preparation of solanidine-derived glycosides and oligosaccharides as insecticides
Beaulieu, R.; Attoumbre, J.; Gobert-Deveaux, V.; Grand, E.; Stasik, I.; Kovensky, J.; Giordanengo, P.
2015, 56pp.; Chemical Indexing Equivalent to 162:219449 (FR).
The claimed synthesized solanidine derivs. I, where X = O or S and R1 = saccharidic or thiosaccharidic side-chain with 1-10 pentose and/or hexose units (esp. glucosyl, galactosyl and rhamnosyl units). The solanidine derivs. can be synthesized starting from the compd. II. Thus, glycoside I (X = O, R1 = β-glucopyranosyl) was prepd. and tested as insecticide agent against Macrosiphum euphorbiae. The compds. have toxic and/or repellent effects on aphids and other properties, including insecticidal, nematicidal, antiviral, antibacterial, and antifungal activities in agrochem. and pharmaceutical sense. The solanidine derivs. may be used as plant protective agents esp. against aphid pests.

Development of an NMR metabolomics-based tool for selection of flaxseed varieties
Ramsay, A.; Fliniaux, O.; Fang, J.; Molinie, R.; Roscher, A.; Grand, E.; Guillot, X.; Kovensky, J.; Fliniaux, M.-A.; Schneider, B.; Mesnard, F.
Metabolomics 2014, 10, 1258-1267.
Flaxseed is an important source of lignans and ω-3 fatty acids, compounds which present interest in human health with many applications in food industry. It is therefore necessary to precisely know the metabolite content in flaxseed. A metabolomic approach using NMR was developed to achieve this goal. Due to particular characteristics of flaxseed (high level in oil, high amount in mucilage, and integration of the phenolics into a macromolecule), the extraction procedure had first to be optimized using an experimental design, based on the extraction time, in a water bath or an ultrasound bath, alkaline treatment, defatting, and centrifugation temperature. This methodology was then applied to several flaxseed varieties classified in function of their content in ω-3 fatty acid. The main differences in semi-polar metabolites between these varieties concern compounds of the phenylpropanoid pathway. Hydroxycinnamic acid glucoside and lignan content increase when ω-3 fatty acid content decrease whereas flavonoid content increase in the same way of ω-3 fatty acids.

Chapter 11 Anionic oligosaccharides: synthesis and applications
Grand, E.; Kovensky, J.; Pourceau, G.; Toumieux, S.; Wadouachi, A.
Carbohydrate Chemistry: Volume 40 2014, 40, 195-235.

Microwave-Assisted Extraction of Herbacetin Diglucoside from Flax (Linum usitatissimum L.) Seed Cakes and Its Quantification using an RP-HPLC-UV System
Fliniaux, O.; Corbin, C.; Ramsay, A.; Renouard, S.; Beejmohun, V.; Doussot, J.; Falguières, A.; Ferroud, C.; Lamblin, F.; Lainé, E.; Roscher, A.; Grand, E.; Mesnard, F.; Hano, C.
Molecules 2014, 19, 3025.
Flax (Linum usitatissimum L.) seeds are widely used for oil extraction and the cold-pressed flaxseed (or linseed) cakes obtained during this process constitute a valuable by-product. The flavonol herbacetin diglucoside (HDG) has been previously reported as a constituent of the flaxseed lignan macromolecule linked through ester bonds to the linker molecule hydroxymethylglutaric acid. In this context, the development and validation of a new approach using microwave-assisted extraction (MAE) of HDG from flaxseed cakes followed by quantification with a reverse-phase HPLC system with UV detection was purposed. The experimental parameters affecting the HDG extraction yield, such as microwave power, extraction time and sodium hydroxide concentration, from the lignan macromolecule were optimized. A maximum HDG concentration of 5.76 mg/g DW in flaxseed cakes was measured following an irradiation time of 6 min, for a microwave power of 150 W using a direct extraction in 0.1 M NaOH in 70% (v/v) aqueous methanol. The optimized method was proven to be rapid and reliable in terms of precision, repeatability, stability and accuracy for the extraction of HDG. Comparison with a conventional extraction method demonstrated that MAE is more effective and less time-consuming.