Guy Jaurand

First Synthetic Carbohydrates with the Full Anticoagulant Properties of Heparin

A single disaccharide building block is required to obtain synthetic carbohydrates that reproduce the anticoagulant activity of heparin and inhibit thrombin (n>6) and/or factor Xa (n≥2; see reaction scheme). Thus, there is evidence that heparin fragments with at least 15 saccharide units are required for thrombin inhibition. Lev=levulinoyl.

Biologically active heparin-like fragments with a “non-glycosamino”glycan structure. Part 3 : o-alkylated-o-sulphated pentasaccharides.

Abstract The synthesis of analogues of biologically active heparin pentasaccharide fragments is reported. Replacement of N-sulphate by O-sulphate esters and introduction of various O-alkyl ethers resulted in biologically active “non-glycosamino“glycans. The biological activity can be further modulated by changing the nature and the position of the alkyl chains introduced.

Identification of a hexasaccharide sequence able to inhibit thrombin and suitable for 'polymerisation'.

Three hexasaccharides, having from low to very high affinity for antithrombin, were synthesised from disaccharide building block precursors. One of them, methyl(sodium 2,3-di-O-methyl-4-O- sodium sulfonato-alpha-L-idopyranosyluronate)-(1-->4)-[(2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranosyl)-(1-->4)-(sodium 2,3-di-O-methyl-alpha-L-idopyranosyluronate)-(1-->4)]2-2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranoside, obtainable from a single disaccharide building block precursor, constitutes a good starting point for obtaining simple oligosaccharidic heparin mimetics able to inhibit the two coagulation factors thrombin and Factor Xa.

Biologically active heparin-like fragments with a “non-glycosamino”glycan structure. Part 1: a pentasaccharide containing a 3-O-methyl iduronic acid unit.

Abstract We describe a new approach towards biologically active analogues of glycosaminoglycan fragments where N-sulphates are replaced by O-sulphates and free hydroxyls are substituted by alkyl ethers. Here we demonstrate that introduction of a methyl group at the 3 position of L-iduronic acid residue neither affects the AT III mediated anti-factor Xa activity nor alters the conformational properties of a unique haparin pentasaccharide sequence.

Assessment through chemical synthesis of the size of the heparin sequence involved in thrombin inhibition

Deca- to eicosasaccharides having the generic structure methyl(sodium 2,3-di-O-methyl-4-O-sodium sulfonato-alpha-L-idopyranosyluronate)-(1-->4)-[(2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranosyl)-(1-->4)-(sodium 2,3-di-O-methyl-alpha-L-idopyranosyluronate)-(1-->4)]n-2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranoside have been synthesized from a single disaccharide precursor. All of them bind to and activate antithrombin. When n < or = 6 only Factor Xa inhibition is observed, whereas when n > 6 Factor Xa and thrombin are both inhibited in the presence of antithrombin. These results indicate that, in heparin, the sequence involved in antithrombin-catalyzed thrombin inhibition is a pentadeca- or a hexadecasaccharide.

Synthesis of a dermatan sulphate-like hexasaccharide with a “non-glycosamino” glycan structure

Abstract The synthesis of a “non-glycosamino” glycan counterpart (i.e. compound II ) of a naturally occuring dermatan sulphate hexasaccharide that binds with high affinity to heparin cofactor II is described.

Die ersten synthetischen Kohlenhydrate mit den vollständigen antikoagulierenden Eigenschaften von Heparin

Ausgehend von einem einzigen Disaccharidbaustein wurden synthetische Kohlenhydrate erhalten, die die gerinnungshemmende Aktivitat von Heparin aufweisen und Thrombin (n>6) und/oder Faktor Xa (n≥2) inhibieren (siehe Schema). Damit ist auch ein Hinweis darauf gegeben, das fur die Inhibierung von Thrombin Heparinfragmente aus mindestens 15 Zuckereinheiten erforderlich sind. Lev = Lavulinoyl.