Vincent Chagnault

Novel sulfated and sulfonated thiodisaccharides, and their multivalent derivatives, as efficient heparanase inhibitors.

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.

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.

Design and synthesis of the first sulfated thiodisaccharide, analog of a heparane sulfate sequence, which is able to inhibit heparanase with an IC ₅₀ in the micromolar range.

Many preparations of maltooligosaccharides have been described in literature, essentially using enzymatic or biotechnological processes. These compounds, derived from starch, are well-known as prebiotic agents. The use of maltohexa-, hepta-, and octaoses as synthons in organic synthesis was also well documented in literature. They can indeed be obtained as single compounds by the cyclodextrins’ ring-opening. This reaction has been studied for many years, varying the protecting and functional groups and the reaction conditions, leading to functionalized oligomaltoses. These compounds are of wide interest in various fields. They have a strong potential as scaffolds for multivalence in chemobiology, as building blocks for the production of biomimetic pseudo-glycopeptides, as well as monomers for the preparation of materials. In view of the importance of these oligomaltoses, this review focuses on the different methodologies allowing access to them via chemical and enzymatic ring-opening of cyclodextrins.

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 on 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.