Abstract
One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy-L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable 1C4 chair conformation of their 6-deoxy-L-talopyranoside residues.
Highlights
Venous thromboembolism is a major cause of mortality and morbidity in the western countries, and epidemiological studies indicate that the aging of the population will increase the incidence of this illness worldwide[1,2]
Heparin and heparinoid anticoagulants exert their anticoagulant activity by binding and activation of antithrombin (AT) which is an endogenous inhibitor of serine proteases in the coagulation cascade[51]
It has been known that plasticity of the L-iduronic acid unit of heparin, an easy shift from the equilibrium state of the preferred 1C4 and 2SO conformations to the 2SO skew-boat form, is crucial for the stabilization of the activated conformation of AT36,52
Summary
Venous thromboembolism is a major cause of mortality and morbidity in the western countries, and epidemiological studies indicate that the aging of the population will increase the incidence of this illness worldwide[1,2]. We envisioned that replacing the IdoA with a more available sugar unit would solve the problem and L-talopyranuronic acid could be a good candidate as a potential structural substituent It is known, that a unique conformational plasticity of the L-iduronic acid, shift the 1C4 - 2SO equilibrium to the bioactive 2SO skew-boat conformation, is required for the antithrombotic activity[36] and it was shown, that its conformation is regulated by the sulphation pattern of nearby saccharides[14,37]. An attractive, short synthesis of L-talopyranosyl thioglycoside, ready for glycosylation has been developed recently[38] This method, based on iridium-catalyzed CH-activation of the corresponding 6-deoxy derivative[39] can potentially utilize in the synthesis of the L-talopyranuronic acid-containing heparinoid oligosaccharides. We report the synthesis and NMR-based conformational analysis of three idraparinux analogue pentasaccharides (2–4) in which the iduronic acid unit (unit G) is substituted by a 6-deoxy-L-talopyranoside moiety (Fig. 1)
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