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Tel : 03 22 82 88 12
Fax : 03 22 82 75 60
Nos travaux portent sur la valorisation des substrats issus de la biomass et plus spécifiquement la valorisation des sucres et de leurs dérivés. Je m'intéresse particulièrement à la découverte de nouveaux outils, de nouvelles réactions, pour faciliter la transformation de ces molécules vers des produits à plus haute valeur ajoutée. Actuellement nous développons deux axes:
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 |
Metal-free hydroxy and aminocyanation of furanos-3-uloses |
Ring-Opening of Cyclodextrins: An Efficient Route to Pure Maltohexa-, Hepta-, and Octaoses |
Design, Synthesis and Antibacterial Activity Evaluation of 4,5-Diphenyl-1H-Imidazoles Derivatives |
Effects of CoCl2 on the regioselective tosylation of oligosaccharides |
Synthesis and interfacial properties of new 6-sulfate sugar-based anionic surfactants |
Physicochemical, foaming and biological properties of lowly irritant anionic sugar-based surfactants |
Synthesis of multivalent S-glycosides analogs of a heparan sulfate sequence |
Preparation of nucleoside derivative carrying an isothiazole or oxathiole cycle with an antiproliferative activity |
Metal-free oxidative esterification of benzylated monosaccharides |
Water-mediated synthesis of disubstituted 5-aminopyrimidines from vinyl azides under microwave irradiation |
Measurement of cytotoxicity and irritancy potential of sugar-based surfactants on skin-related 3D models |
Physico-chemical properties and cytotoxic effects of sugar-based surfactants: Impact of structural variations |
Reactivity of D-fructose and D-xylose in acidic media in homogeneous phases |
Metal-Free Oxidative Lactonization of Carbohydrates Using Molecular Iodine |
Metal-Free, Diamine-Mediated, Oxidative Monoamidation of Benzylated Carbohydrates |
Synthesis of glycosylamines and glyconamides using molecular iodine |
Metal-free oxidative lactonization of carbohydrates using molecular iodine |
Synthesis of 1,5-di-C-alkyl 1,5-iminoxylitols related to 1-deoxynojirimycin |
Biological study of a somatostatin mimetic based on the 1-deoxynojrimycin scaffold |
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.
TSAO-T and ATSAO-T analogues are molecules of interest that are able to inhibit the reverse transcriptase (RT) of HIV-1 and HCV. We also recently highlighted their antiproliferative properties. In all cases, the spiro cycle was a required group for biological activities, which led chemists to produce many derivatives, especially on this ring. These structures can be accessed through the formation of glycoaminonitriles and glycocyanhydrins using methodologies not always adapted to the synthesis of large quantities. Moreover, these latter are poorly versatile (substrate-dependent), need expensive cyanogenic agents and implies the use of a metal in non-catalytic amounts. For this reason, we report here a new metal-free methodology for the synthesis of glycoaminonitriles and glycocyanhydrins using molecular iodine (I2).
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.
Three families of anionic sugar-based surfactants bearing a sulfate functional group on the primary position of a monosaccharide were synthesized and their physicochemical properties were compared. The first family corresponds to 6-sulfate derivatives of commercially available octa- and dodecyl β-D-gluco- and galactopyranosides. The second and the third families contain an amide linker between the sulfated monosaccharide (galactose, glucose or xylose) and the hydrophobic alkyl chain. Twelve of the as-synthesized anionic glycolipids, including nine novel sulfated compounds, were investigated for their surface activity at the air/liquid interface and for their self-assembling properties. These sugar-based surfactants show surface properties similar to those of commercial anionic surfactants (SDS and SLES) with good ability to reduce surface tension. The obtained results confirm the interest in these new bio-based molecules for potential substitution of anionic surfactants in various formulations.
Surface-active compounds derived from biomass, especially sugar-based amphiphiles, have received wide attention regarding their biodegradability, low toxicity and ecological acceptability. Compared to nonionic sugar-based surfactants, the anionic ones show significantly better solubility, higher surface activity and foaming performance. Thus they are largely used in personal care formulations and many technological applications. However, anionic surfactants are well known to induce skin and eye irritation. In this study, three sugar-based anionic surfactants, bearing a lipidic chain grafted to the anomeric position of a monosaccharide (glucose or xylose) and a sulfate group on the primary hydroxyl, were synthesized: 6-O-sulfo-N-(β-d-glucopyranosyl) dodecanamide (GlcNC12S), N-dodecyl-6-O-sulfo-d-gluconamide (GlcCC12S) and N-dodecyl-6-O-sulfo-d-xylonamide (XylCC12S). These molecules were investigated in details for their self-assembling behavior, foaming properties and biological effects. All their properties were compared to those of two commercially available anionic surfactants, sodium laureth sulfate (SLES) and sodium dodecylsulfate (SDS). Results revealed that the three anionic glycolipids show surface properties and foaming behavior comparable to those of SDS. Furthermore, their cytotoxic and irritation potentials are significantly lower compared to commercial molecules, which make these renewable molecules potential candidates for replacement of petroleum-based compounds.
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.
Methyl glyconates have been attracting considerable attention as intermediates for the preparation of aryl C-glycosides, polyphenolic products, aliphatic polyesters, SGLT2 inhibitors, antibiotics etc … In view of the interest in those compounds, we report herein our work on the synthesis of methyl glyconates using an oxidative esterification carried out by molecular iodine. This reaction is catalyzed by non-toxic K4Fe(CN)6 that releases a small amount of cyanide ion into the reaction mixture. Four benzylated carbohydrates which contain a hemiacetalic functional group have been tested successfully.
An efficient and ecofriendly method for the synthesis of disubstituted 5-aminopyrimidines from vinyl azides and urea or thiourea was developed. This reaction proceeds under microwave irradiation conditions in the presence of water as a solvent. The remarkable features of this new protocol are high conversion, short reaction times, cleaner reaction profiles and straightforward procedure.
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.
Chemistry development of renewable resources is a real challenge. Carbohydrates from biomass are complex and their use as substitutes for fossil materials remains difficult (European involvement on the incorporation of 20% raw material of plant origin in 2020). Most of the time, the transformation of these polyhydroxylated structures are carried out in acidic conditions. Recent reviews on this subject describe homogeneous catalytic transformations of pentoses, specifically toward furfural, and also the transformation of biomass-derived sugars in heterogeneous conditions. To complete these informations, the objective of this review is to give an overview of the structural variety described during the treatment of two monosaccharides (D-Fructose and D-xylose) in acidic conditions in homogeneous phases. The reaction mechanisms being not always determined with certainty, we will also provide a brief state of the art regarding this.
We describe herein the synthesis of glyconamides and glycosylamines using mol. iodine on benzylated carbohydrates. During the improvement and the optimization of the direct oxidative amidation reaction, we also discovered the possibility to form glycosylamines with excellent yields and short reaction times in comparison with the previously reported procedures. Advantages of these methods are the operational simplicity, elimination of use of complicated reagents and procedures, and generality of the reactions. Our methodol. is an excellent access to precursors of N-alkyliminosugars and imino-C-glycosides. 
We describe herein the oxidative lactonization of fully or partially protected carbohydrates using mol. iodine. Oxidn. of aldose hemiacetals is generally carried out by classical procedures, which are rarely chemo or regioselective. We recently reported an optimized methodol. for the oxidative amidation of aldose with functionalized amines and we found mol. iodine as a good selective oxidant. This property has been already obsd. by other research groups but the scope of this reactivity has never been studied for carbohydrates. The main advantage of this approach relies on the operational simplicity, elimination of use of complicated reagents and procedures. 
Previously the synthesis of novel somatostatin mimetic from 1-deoxynojrimycin (DNJ) led to identification of a compd. with affinity for human somatostatin receptor subtypes 4 and 5 (hSSTR4 and hSSTR5). Here we examd. the properties of this peptidomimetic in a human umbilical vein endothelial cell (HUVEC) based assays. The peptidomimetic prevented capillary tube formation based on HUVECs. It also inhibited HUVEC proliferation by inducing G1 phase cell cycle arrest and apoptosis. Stress fiber assembly and cell migration in HUVECs was markedly suppressed by the somatostatin receptor ligand.