Science (American Association for the Advancement of Science), 2011-10, Vol.334 (6055), p.498-501
2011
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- Autor(en) / Beteiligte
- Titel
- Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins
- Ist Teil von
- Science (American Association for the Advancement of Science), 2011-10, Vol.334 (6055), p.498-501
- Ort / Verlag
- Washington, DC: American Association for the Advancement of Science
- Erscheinungsjahr
- 2011
- Quelle
- American Association for the Advancement of Science
- Beschreibungen/Notizen
- Ultralow molecular weight (ULAAW) 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0036-8075eISSN: 1095-9203DOI: 10.1126/science.1207478Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3425363
- Format
- –
- Schlagworte
- Animals, Anticoagulants, Anticoagulants - chemical synthesis, Anticoagulants - chemistry, Anticoagulants - pharmacokinetics, Anticoagulants - pharmacology, Antithrombins - chemistry, Antithrombins - metabolism, Binding Sites, Biochemistry, Biological and medical sciences, Blood. Blood coagulation. Reticuloendothelial system, Chemical Phenomena, Chemical synthesis, Chemistry, Disaccharides, Disorders, Enzymes, Fondaparinux, Glycan, Glycosyltransferases - metabolism, Heparan sulfate, Heparin, Heparin, Low-Molecular-Weight - chemical synthesis, Heparin, Low-Molecular-Weight - chemistry, Heparin, Low-Molecular-Weight - pharmacokinetics, Heparin, Low-Molecular-Weight - pharmacology, Heparins, Medical sciences, Molecular Structure, Molecular Weight, N-Acetylglucosaminyltransferases - metabolism, Oligosaccharides, Oligosaccharides - chemistry, Pharmacokinetics, Pharmacology. Drug treatments, Polysaccharides, Polysaccharides - chemistry, Polysaccharides - pharmacokinetics, Polysaccharides - pharmacology, Protons, Rabbits, Racemases and Epimerases - metabolism, Sodium, Spectrometry, Mass, Electrospray Ionization, Substrate Specificity, Sulfotransferases - metabolism, Synthesis