Chemoenzymatic synthesis of heparin oligosaccharides

Authors
Harvey, Catherine Malinda
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Other Contributors
Linhardt, Robert J.
McGown, Linda Baine
Bailey, R. A. (Ronald Albert), 1933-
Issue Date
2013-08
Keywords
Chemistry
Degree
MS
Terms of Use
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.
Full Citation
Abstract
Heparin is a highly sulfated glycosaminoglycan; a heterogeneous polysaccharide that exhibit anticoagulant activity. The commercial drug, Arixtra (fondaparinux sodium), is a structurally homogeneous heparin pentasaccharide (an ultralow molecular weight heparin). The current chemical synthesis is rather lengthy (≈50 steps) and low-yielding (<1%). A promising alternative approach developed by our laboratory and others is to chemoenzymatically synthesize heparins utilizing both uridine diphosphate sugars as electrophilic donors and the para-nitrophenyl β-glucuronide as the initial nucleophilic acceptor; this commercially available monosaccharide acceptor is conformable to enzymatic elongation, conducive to the purification of these oligosaccharides with a C-18 column, and cleavable with ceric ammonium sulfate. Fondaparinux synthesis requires a backbone structure of defined size that can be specifically N-sulfonated and selectively modified by the heparan sulfate sulfotransferases and C5-epimerase. This thesis describes efforts to chemoenzymatically synthesize heparan sulfate oligosaccharide backbones, key intermediates in the synthesis of an Arixtra analog.
Description
August 2013
School of Science
Department
Dept. of Chemistry and Chemical Biology
Publisher
Rensselaer Polytechnic Institute, Troy, NY
Relationships
Rensselaer Theses and Dissertations Online Collection
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