Synthese konformativ fixierter Kohlenhydrate: Eine Skew-Bootkonformation derL-Iduronsäure in Heparin bestimmt dessen antithrombotische Aktivität

We have used organic synthesis to understand the role of L-iduronic acid conformational flexibility in the activation of antithrombin by heparin. Among known synthetic analogues of the genuine pentasaccharidic sequence representing the antithrombin binding site of heparin, we have selected as a reference compound the methylated anti-factor Xa pentasaccharide 1. As in the genuine original fragment, the single L-iduronic acid moiety of this molecule exists in water solution as an equilibrium between three conformers 1C4, 4C1 and 2S0. We have thus synthesized three analogues of 1, in which the L-iduronic acid unit is locked in one of these three fixed conformations. A covalent two atom bridge between carbon atoms two and five of L-iduronic acid was first introduced to lock the pseudorotational itinerary of the pyranoid ring around the 2S0 form. A key compound to achieve this connection was the D-glucose derivative 5 in which the H-5 hydrogen atom has been replaced by a vinyl group, which is a progenitor of the carboxylic acid. Selective manipulations of this molecule resulted in the 2S0-type pentasaccharide 23. Starting from the D-glucose derivative 28, a covalent two atom bridge was now built up between carbon atoms three and five to lock the L-iduronic acid moiety around the 1C4 chair form conformation, and the 1C4-type pentasaccharide 43 was synthesized. Finally the L-iduronic acid containing disaccharide 58 which, due to the presence of the methoxymethyl substituent at position five adopts a 4C1 conformation, was directly used to synthesize the 4C1-type pentasaccharide 61. The locked pentasaccharide 23 showed about the same activity as the reference compound 1 in an antithrombin-mediated anti-Xa assay, whereas the two pentasaccharides 43 and 61 displayed very low activity. These results clearly establish the critical importance of the 2S0 conformation of L-iduronic acid in the activation of antithrombin by heparin.

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Synthesis of Conformationally Lockedl-Iduronic Acid Derivatives: Direct Evidence for a Critical Role of the Skew-Boat2S0 Conformer in the Activation of Antithrombin by Heparin

Das

Mallet

Esnault

et al. 2001

Chem. Eur. J.

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The Construction of Anhydro Monosaccharides

Xie

Lin

et al. 2016

Asian J Org Chem

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Anhydro monosaccharide is as pecific and distinctive category of carbohydrates, which is found in many naturally deriveda nd artificial bioactive substrates. In the field of organic chemistry,s ome anhydro sugars can be used as common synthons to construct different carbohydrate structures. The development of efficient methodologies for the constructiono fv ariousa nhydro sugar fragments is very important in carbohydrate chemistry,w hich has attracted considerable attention in the past few years. This reviewm ainly covers the development of new synthetic methods since 2000 and gives an overview of the development in the formation of anhydro monosaccharide structures. It systematically summarizes all methodst oe stablish an intramolecular ether bridge in furanose and pyranose structures, which are the mostc ommonly used monosaccharide fragments in carbohydrate chemistry.

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Ein synthetisches Antithrombin III bindendes Pentasaccharid ist jetzt ein Wirkstoff! Was kommt danach?

Petitou

Boeckel²

2004

Angewandte Chemie

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Heparin, ein aus tierischen Organen gewonnenes sulfatiertes Glycosaminoglycan, findet seit den 40er Jahren als antithrombotischer Wirkstoff klinische Verwendung. Ein Durchbruch in der Heparinforschung war in den frühen 80er Jahren die Entdeckung, dass eine charakteristische Pentasacchariddomäne in manchen Heparinketten den Serinproteaseinhibitor Antithrombin III (AT‐III) aktiviert, der in der Gerinnungskaskade Thrombin und den Faktor Xa inhibiert. Sanofi‐Synthélabo und Organon entwickelten das Analogon 2 (Fondaparinux) des Pentasaccharids. Die Verbindung wurde zum antithrombotischen Medikament Arixtra weiterentwickelt, das 2002 in den USA und Europa auf den Markt kam. Arixtra bewirkt ausschließlich die AT‐III‐vermittelte Inhibierung des Faktors Xa. Durch strukturbezogenes Design wurden auch Analoga mit längerer Wirkungsdauer wie Idraparinux sowie neue Konjugate und lange Oligosaccharide mit spezifischer Anti‐Xa‐ und Antithrombin‐Aktivität zugänglich. Die neuen Wirkstoffkandidaten wirken selektiver als Heparin, was insbesondere die Wahrscheinlichkeit einer Thrombopenie verringert.

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Synthese konformativ fixierter Kohlenhydrate: Eine Skew-Bootkonformation derL-Iduronsäure in Heparin bestimmt dessen antithrombotische Aktivität

Cited by 18 publications

References 24 publications

Synthesis of Conformationally Lockedl-Iduronic Acid Derivatives: Direct Evidence for a Critical Role of the Skew-Boat2S0 Conformer in the Activation of Antithrombin by Heparin

Synthesis of Conformationally Lockedl-Iduronic Acid Derivatives: Direct Evidence for a Critical Role of the Skew-Boat2S0 Conformer in the Activation of Antithrombin by Heparin

The Construction of Anhydro Monosaccharides

Ein synthetisches Antithrombin III bindendes Pentasaccharid ist jetzt ein Wirkstoff! Was kommt danach?

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