Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Anticoagulants / chemical synthesis*
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Anticoagulants / chemistry
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Anticoagulants / pharmacokinetics
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Anticoagulants / pharmacology
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Antithrombins / chemistry
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Antithrombins / metabolism
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Binding Sites
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Chemical Phenomena
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Fondaparinux
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Glycosyltransferases / metabolism
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Heparin, Low-Molecular-Weight / chemical synthesis*
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Heparin, Low-Molecular-Weight / chemistry
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Heparin, Low-Molecular-Weight / pharmacokinetics
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Heparin, Low-Molecular-Weight / pharmacology
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Molecular Structure
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Molecular Weight
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N-Acetylglucosaminyltransferases / metabolism
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Oligosaccharides / chemistry
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Polysaccharides / chemistry
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Polysaccharides / pharmacokinetics
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Polysaccharides / pharmacology
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Rabbits
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Racemases and Epimerases / metabolism
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Spectrometry, Mass, Electrospray Ionization
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Substrate Specificity
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Sulfotransferases / metabolism
Substances
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Anticoagulants
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Antithrombins
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Heparin, Low-Molecular-Weight
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Oligosaccharides
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Polysaccharides
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Glycosyltransferases
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N-Acetylglucosaminyltransferases
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heparosan synthase
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N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase
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Sulfotransferases
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Racemases and Epimerases
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Fondaparinux