Synthetic heparin pentasaccharide

Dermatan sulfete and heparan sulfitte have provided disappointing results to date. The synthetic heparin pentasaccharide, which acts strictly via die inhibition of fector Xa, has been successfidly used in angioplasty and is presently imdergoing clinical trial for the prophylaxis of venous thrombosis in orthope c surgical patients. Various large scale clinicd trials have been organized. In addition, several derivatives of oligosaccharides are also developed with multiple protease inhibitory action. 

Walenga JM, Jeske WP, Samama MM, Frapaise FX, Bick RL, Fareed J. Fondaparinux a synthetic heparin pentasaccharide as a new antithrombotic agent. Expert Opin Investig Drugs 2002 11(3) 397 I07. 

The anticoagulant fondaparinux, a synthetic analogue of the terminal fragment of heparin, is synthesized using multiple protection/deprotection steps that result in a route of up to 50 steps. There is, as yet, no enzymatic system that approaches the capability to make such a molecule." As this modified pentasaccharide is a natural product, it should, in theory, be accessible through a series of biotransformations, but we currently lack the biocatalytic tools to achieve more than a few steps and would stiU need to use some protection steps to avoid multiple products. Enzymatic synthesis in vivo depends largely on the levels and selectivities of glycosylating enzymes to achieve multistep reactions, a situation that has been mimicked in vitro for simpler systems." ... 

Fondaparinux sodium is the first of a new class of direct-acting antithrombin agents. The anticoagulant activity of heparin depends on the binding of ATIII to a critical pentasaccharide sequence within the heparin molecule. This results in a change in the conformation of AITII. This leads to the inhibitory effect of ATIII on factor Xa, which activates the conversion of prothrombin to thrombin. Fondaparinux is a synthetic pentasaccharide identical to the ATIII-binding site of heparin. 

FIGURE 12.4 Structures of the complexes between different SPs and AT. (A) Ternary complex between AT, thrombin, and an heparin derivative (PDB ID 1TB6) (B) AT bounded to the synthetic pentasaccharide (PDB ID 1E03) (C) final structure from a 5-ns MD of AT complexed to a SF decasaccharide with pyranose rings (D) final structure from a 5-ns MD of AT complexed to a SG decasaccharide with pyranose rings. For (B)-(D), two orientations of the complexes are presented. Data from Becker et al. (2007). 

The indirect thrombin inhibitors are so named because their antithrombotic effect is exerted by their interaction with antithrombin. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the synthetic pentasaccharide fondaparinux bind to antithrombin and enhance its inactivation of factor Xa. UFH and to a lesser extent LMWH also enhance antithrombin s inactivation of thrombin (Ha). 

Pre-clinical studies indicate that neutralase can also inactivate the anticoagulant effects of the low LMW heparins and the synthetic pentasaccharide fondaparinux (10) (see... 

The completed polymers are modified uniformly There are clusters of sulfo groups with imusual stmctures in chondroitin from squid and shark cartilages and fucosylated chondroitin from echinoderms. Similar modifications are present less extensively in vertebrates. One of the best known modifications forms the unique pentasaccharide sequence shown in Fig. 4-13, which is essential to the anticoagulant activity of heparin. This sequence has been synthesized in the laboratory as have related longer heparin chains. A sequence about 17 residues in length containing an improved synthetic version of the imique pentasaccharide binds tightly to both thrombin and antithrombin (Chapter 12, Section This... 

C30H51N3O49S8 1494.252 Synthetic pentasaccharide representing the antithrombin III binding site of heparin. Antithrombotic agent the first synthetic material having a high binding affinity for antithrombin III. [ajp +42 (c, 1.0 in H2O) (as di-Na salt). 

A synthetic 3-0-sulfated pentasaccharide, representing heparin s ATIII binding site (Figure 3) was first prepared by Choay, et.al., in a multi-step synthesis.24 clinical studies on this pentasaccharide, as an antithrombotic agent, demonstrated that it was not as effective as heparin itself and its cost probably precludes its use as a therapeutic... 

This synthetic pentasaccharide and analogues are potential antithrombotic drugs devoid of certain detrimental side effects when compared with natural standard heparin [24],... 

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