Chemoenzymatic synthesis of heparin oligosaccharides

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.