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      Synthesis of the Heparin‐Based Anticoagulant Drug Fondaparinux

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          Abstract

          Fondaparinux, a synthetic pentasaccharide based on the heparin antithrombin‐binding domain, is an approved clinical anticoagulant. Although it is a better and safer alternative to pharmaceutical heparins in many cases, its high cost, which results from the difficult and tedious synthesis, is a deterrent for its widespread use. The chemical synthesis of fondaparinux was achieved in an efficient and concise manner from commercially available D‐glucosamine, diacetone α‐ D‐glucose, and penta‐O‐acetyl‐ D‐glucose. The method involves suitably functionalized building blocks that are readily accessible and employs shared intermediates and a series of one‐pot reactions that considerably reduce the synthetic effort and improve the yield.

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          Most cited references36

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          Heparin-Protein Interactions

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            2003 Claude S. Hudson Award address in carbohydrate chemistry. Heparin: structure and activity.

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              Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins.

              Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.
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                Author and article information

                Journal
                Angewandte Chemie International Edition
                Angew Chem Int Ed
                Wiley
                1433-7851
                1521-3773
                September 08 2014
                July 15 2014
                September 08 2014
                : 53
                : 37
                : 9876-9879
                Article
                10.1002/anie.201404154
                25044485
                cddcb299-852a-42a9-855e-5076a15fd545
                © 2014

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