Comparative analysis of sulfated and sulfonated disaccharide analogs as TLR4 modulators and heparanase inhibitors
El-Abid, J.; Koffi Teki, D. S.-E. K. L. C.; Bil, A.; Denys, A.; Vallin, A.; Lefebvre, C.; Allain, F.; Chagnault, V.; Kovensky, J.
New J. Chem. 2024.
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.
https://dx.doi.org/10.1039/D4NJ01326C

Fragmentation of DMPC Membranes by a Wedge-Shaped Amphiphilic Cyclodextrin into Bicellar-like Aggregates
Roux, M.; Legrand, F. X.; Bil, A.; Bonnet, V.; Djedaini-Pilard, F.
J. Phys. Chem. B 2023.
Small bilayer lipid aggregates such as bicelles provide useful isotropic or anisotropic membrane mimetics for structural studies of biological membranes. We have shown previously by deuterium NMR that a wedge-shaped amphiphilic derivative of trimethyl betacyclodextrin anchored in deuterated DMPC-d27 bilayers through a lauryl acyl chain (TrimbetaMLC) is able to induce magnetic orientation and fragmentation of the multilamellar membranes. The fragmentation process fully detailed in the present paper is observed with 20% cyclodextrin derivative below 37 degrees C, where pure TrimbetaMLC self-assembles in water into large giant micellar structures. After deconvolution of a broad composite (2)H NMR isotropic component, we propose a model where the DMPC membranes are progressively disrupted by TrimbetaMLC into small and large micellar aggregates depending whether they are extracted from the outer or inner layers of the liposomes. Below the fluid-to-gel transition of pure DMPC-d27 membranes (T(c) = 21.5 degrees C), the micellar aggregates vanish progressively until complete extinction at 13 degrees C, with a probable release of pure TrimbetaMLC micelles leaving lipid bilayers in the gel phase doped with only a small amount of the cyclodextrin derivative. Bilayer fragmentation between T(c) and 13 degrees C was also observed with 10% and 5% of TrimbetaMLC, with NMR spectra suggesting possible interactions of micellar aggregates with fluid-like lipids of the P(beta') ripple phase. No membrane orientation and fragmentation was detected with unsaturated POPC membranes, which are able to accommodate the insertion of TrimbetaMLC without important perturbation. The data are discussed in relation to the formation of possible DMPC bicellar aggregates such as those known to occur after insertion of dihexanoylphosphatidylcholine (DHPC). These bicelles are in particular associated with similar deuterium NMR spectra exhibiting identical composite isotropic components which were never characterized before.
https://dx.doi.org/10.1021/acs.jpcb.2c07331

Fast and Efficient Mechanosynthesis of Aldonamides by Aminolysis of Unprotected Sugar Lactones
Bil, A.; Abdellahi, B.; Pourceau, G.; Wadouachi, A.
Sustainable Chemistry 2022, 3, 300-311.
Sugar amides, such as aldonamides, are interesting, sugar-based molecules used in various fields, from detergency to medicine. Nevertheless, their valorization, especially as alternatives to petroleum-based substances, can be slowed down by their synthetic pathway, which is generally not in accordance with green chemistry principles, and is also not economically competitive. We propose herein a fast procedure for the synthesis of aldonamide-derived glycoconjugates with mechanochemistry. The conditions were first optimized with galactonolactone, used as a model lactone, and dodecylamine. After only 5 min of grinding of stoechiometric amounts of amine and lactone, in the presence of water used as a Liquid Assisted Grinding (LAG) agent, the corresponding galactonamide was isolated with a high yield (90%) after a simple aqueous work-up. The optimized conditions were then applied to a wide variety of amines and sugar lactones, showing the versatility of the methodology. Gluco- and ribono-lactone exhibited similarly excellent reactivity, showing that the procedure is not sugar-dependent. Furthermore, the procedure was shown to be compatible with various functional groups such as alkene, alkyne, thiol, ester and hydroxyl.
https://dx.doi.org/10.3390/suschem3030019

Synthesis of novel S- and O-disaccharide analogs of heparan sulfate for heparanase inhibition
Koffi Teki, D. S. E.; Coulibaly, B.; Bil, A.; Vallin, A.; Lesur, D.; Fanté, B.; Chagnault, V.; Kovensky, J.
Org. Biomol. Chem. 2022.
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.
https://dx.doi.org/10.1039/d2ob00250g

One-Pot Synthesis of Asymmetrically Difunctionalized Oligomaltosides by Cyclodextrin Ring Opening
Pélingre, M.; Smadhi, M.; Bil, A.; Bonnet, V.; Kovensky, J.
ChemistryOpen 2021, 10, 493-496.
Abstract The synthesis of pure difunctionalized hexa-, hepta- and octamaltosides was performed by one-pot chemical reaction from perbenzoylated cyclodextrin. Oligomaltosides with azide, propargyl or allyl on reducing end and an unprotected hydroxyl group on non-reducing end were obtained from perbenzoylated α-, β- and γ-cyclodextrin with 12 to 48 % yields.
https://doi.org/10.1002/open.202100079

First step to the improvement of the blood brain barrier passage of atazanavir encapsulated in sustainable bioorganic vesicles
Nolay, F.; Sevin, E.; Létévé, M.; Bil, A.; Gosselet, F.; El Kirat, K.; Djedaini-Pilard, F.; Morandat, S.; Fenart, L.; Przybylski, C.; Bonnet, V.
Int. J. Pharm. 2020, 587, 119604.
The blood - brain barrier (BBB) prevents the majority of therapeutic drugs from reaching the brain following intravenous or oral administration. In this context, polymer nanoparticles are a promising alternative to bypass the BBB and carry drugs to brain cells. Amphiphilic cyclodextrins can form self-assemblies whose nanoparticles have a 100-nm-diameter range and are thus able to encapsulate drugs for controlled release. Our goal is to propose an optimized chemical synthesis of amphiphilic cyclodextrin, which remains a challenging task which commonly leads to only a low-milligram level of the high purity compound. Such cyclodextrin derivatives were used to prepare vesicles and to study their ability to vectorize a drug through the BBB. As a result, we introduced a convergent synthesis for a family of lipophosphoramidyl permethylated β-CDs (Lip-β-CDs) with various chain lengths. It was demonstrated that mixed vesicles comprised of phosphatidylcholine (POPC) and LipCDs were able to encapsulate atazanavir (ATV), a well-known protease inhibitor used as an antiretroviral drug against HIV. We highlighted that neo-vesicles promote the penetration of ATV in endothelial cells of the BBB, presumably due to the low fusogenicity of Lip-β-CDs.
https://dx.doi.org/10.1016/j.ijpharm.2020.119604

Solvent- and catalyst-free transamidations of unprotected glycosyl carboxamides
Bensalah, F. O.; Bil, A.; Wittine, K.; Bellahouel, S.; Lesur, D.; Markovic, D.; Laclef, S.
Org. Biomol. Chem. 2019.
The transamidation reactions of unprotected mono- and disaccharidic carboxamides with various primary and secondary arylic, heterocyclic or aliphatic amines are described. This new method is green and atom efficient and gives good to high yields. Notably, the conditions do not require either a solvent or a catalyst and give ammonia as a single by-product. The described coupling reaction is compatible with a variety of functional groups and was used in the synthesis of various glycosidic derivatives and biologically relevant glycolipids. A plausible reaction mechanism involving an intermolecular H-bond activation of the starting carboxamides is proposed.
https://dx.doi.org/10.1039/C9OB02096A

Uncommon Strong Inhibition of α-Glucosidase by Multivalent Glycoclusters built on Cyclodextrins Scaffolds
Alali, U.; Vallin, A.; Bil, A.; Khanchouche, T.; Mathiron, D.; Przybylski, C.; Beaulieu, R. R.; Kovensky, J.; Benazza, M.; Bonnet, V.
Org. Biomol. Chem. 2019.
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.
https://dx.doi.org/10.1039/C9OB01344J

Synthesis of multivalent S-glycosides analogs of a heparan sulfate sequence
Koffi Teki, D. S.-E.; Bil, A.; Moreau, V.; Chagnault, V.; Fanté, B.; adjou, a.; Kovensky, J.
Organic Chemistry Frontiers 2019.
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.
https://dx.doi.org/10.1039/C9QO00581A

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.
http://dx.doi.org/10.1016/j.chemosphere.2018.11.025

Metal-free oxidative esterification of benzylated monosaccharides
Camara, T.; Bil, A.; Chagnault, V.
Carbohydr. Res. 2018.
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.
https://doi.org/10.1016/j.carres.2018.04.003