Chemoenzymatic synthesis of heparin oligosaccharides
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Authors
Harvey, Catherine Malinda
Issue Date
2013-08
Type
Electronic thesis
Thesis
Thesis
Language
ENG
Keywords
Chemistry
Alternative Title
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
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY