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


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Sylvestre TOUMIEUX

Maître de conférences

Mail :

Tel : 03 22 82 74 76

Fax : 03 22 82 75 60

Axe de recherche : Chimie pour le Développement Durable

Description des travaux de recherche

La thématique développée concerne la synthèse de nouveaux composés polysaccharidiques et en particulier les glycoaminoglycanes (GAG). Cette famille de polysaccharide est présente dans les tissus biologiques de nombreux organismes vivants (humains, bactéries). Ces GAGs jouent un rôle fondamental dans des phénomènes physiologiques (reconnaissance, développement et croissance) ou pathologiques (inflammation, métastase). Ils constituent alors une cible de choix pour le traitement de pathologies variées.

Nous cherchons alors à synthétiser de nouveaux oligosaccharides anioniques qui puissent mimer les substrats naturels en variant la nature de la liaison glycosidique, en modulant la position des groupements anioniques et en apportant des modifications aussi bien de nature stéréochimiques que fonctionelles sur l’unité saccharidique.

Pour ce faire nous utilisons des méthodes modernes de synthèse organique comme la fonctionnalisation régio- et stéréosélective, l’introduction de la diversité structurale via des voies de synthèse divergentes et non-linéaires et tout en limitant notre impact environnemental (C-H activation, absence de groupes protecteurs, micro-onde).

Mots clés : N.C.

Sélection de publications

Mechanochemical synthesis of (4S)-N-alkyl-4,5-bis-sulfooxypentanamide via a one-pot sequential aminolysis-sulfation reaction of (S)-γ-hydroxymethyl-γ-butyrolactone (2H-HBO)
Herrlé, C.; Toumieux, S.; Araujo, M.; Peru, A.; Allais, F.; Wadouachi, A.
Green Chem. 2022.
To valorize further the highly valuable bio-based platform (S)-γ-hydroxymethyl-γ-butyrolactone (2H-HBO), whose sustainable kiloscale-synthesis from cellulose-derived levoglucosenone (LGO) has been validated, a mechanochemical strategy was developed to produce new potential bio-based surfactants under solventless conditions. First, the reaction of 2H-HBO with primary or secondary amines was investigated followed by a sulfation reaction with the isolated N-alkyl-amide derivatives to obtain the corresponding N-alkyl sulfated compounds. The latter was then obtained by an optimized one-pot sequential aminolysis–sulfation in a planetary ball mill with excellent efficiency. For the first time, sulfated compounds arising from bio-based/renewable resources were obtained exclusively via a mechanochemical process. As a result, the sulfated derivatives of 2H-HBO were formed quantitatively and isolated in 69–79% overall yields. The critical micelle concentration (CMC) was determined for some of them which exhibited interesting anionic surfactant properties.

Synthesis of new sulfated disaccharides for the modulation of TLR4-dependent inflammation
Naitaleb, R.; Denys, A.; Allain, F.; Ausseil, J.; toumieux, s.; Kovensky, J.
Org. Biomol. Chem. 2021.
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.

First Sustainable Aziridination of Olefins Using Recyclable Copper-Immobilized Magnetic Nanoparticles
Toumieux, S.; Khodadadi, M.; Pourceau, G.; Becuwe, M.; Wadouachi, A.
Synlett 2019, 30, 563-566.
The first copper-catalyzed aziridination of olefins using recyclable magnetic nanoparticles is described. Magnetic nanoparticles were modified with dopamine and used as a support to coordinate copper. The methodology was optimized with styrene as olefin and using [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI=NTs) as nitrene source. A microwave irradiation decreased the reaction time by 4-fold compared to conventional heating method. The catalyst was recovered by simple magnetic extraction and could be reused successfully up to five times without significant loss of activity. The methodology was applied to a range of different olefins leading to moderate to excellent yields in the formation of the expected aziridine.

Efficient Synthesis of N-Alkyl Polyhydroxylated Pipecolamide Compounds from d-Glucurono-6,3-lactone
Kaddour, A.; Toumieux, S.; Wadouachi, A.
Synlett 2017, 28, 2174-2178.
N-Alkyl pipecolamides were efficiently synthesized from d-glucurono-6,3-lactone via a key 5-azido N-alkylamide intermediate that can be used as a scaffold for the synthesis of 4-amino and N-sulfonated pipecolamide derivatives.

Oligogalacturonic Acid Inhibits Vascular Calcification by Two Mechanisms: Inhibition of Vascular Smooth Muscle Cell Osteogenic Conversion and Interaction With Collagen
Hodroge, A.; Trecherel, E.; Cornu, M.; Darwiche, W.; Mansour, A.; Ait-Mohand, K.; Verissimo, T.; Gomila, C.; Schembri, C.; Da Nascimento, S.; Elboutachfaiti, R.; Boullier, A.; Lorne, E.; Courtois, J.; Petit, E.; Toumieux, S.; Kovensky, J.; Sonnet, P.; Massy, Z. A.; Kamel, S.; Rossi, C.; Ausseil, J.
Arterioscler Thromb Vasc Biol 2017, 37, 1391-1401.
OBJECTIVE: Cardiovascular diseases constitute the leading cause of mortality worldwide. Calcification of the vessel wall is associated with cardiovascular morbidity and mortality in patients having many diseases, including diabetes mellitus, atherosclerosis, and chronic kidney disease. Vascular calcification is actively regulated by inductive and inhibitory mechanisms (including vascular smooth muscle cell adaptation) and results from an active osteogenic process. During the calcification process, extracellular vesicles (also known as matrix vesicles) released by vascular smooth muscle cells interact with type I collagen and then act as nucleating foci for calcium crystallization. Our primary objective was to identify new, natural molecules that inhibit the vascular calcification process. APPROACH AND RESULTS: We have found that oligogalacturonic acids (obtained by the acid hydrolysis of polygalacturonic acid) reduce in vitro inorganic phosphate-induced calcification of vascular smooth muscle cells by 80% and inorganic phosphate-induced calcification of isolated rat aortic rings by 50%. A specific oligogalacturonic acid with a degree of polymerization of 8 (DP8) was found to inhibit the expression of osteogenic markers and, thus, prevent the conversion of vascular smooth muscle cells into osteoblast-like cells. We also evidenced in biochemical and immunofluorescence assays a direct interaction between matrix vesicles and type I collagen via the GFOGER sequence (where single letter amino acid nomenclature is used, O=hydroxyproline) thought to be involved in interactions with several pairs of integrins. CONCLUSIONS: DP8 inhibits vascular calcification development mainly by inhibition of osteogenic marker expression but also partly by masking the GFOGER sequence-thereby, preventing matrix vesicles from binding to type I collagen.

Glycochemical Applications of Diels-Alder Reaction
Laclef, S.; Toumieux, S.; Kovensky, J.
Curr. Org. Chem. 2016, 20, 2379-2392.
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.

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.