A modular approach toward chondroitin sulfate oligosaccharides
Wilkes, Jo-Sette Lynn
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Chondroitin Sulfate (CS) belongs to a class of linear, highly charged, acidic polysaccharides known as glycosaminoglycans (GAGs). It is composed of β (1→4)-linked disaccharide units having a glucuronic acid (GlcA) β (1→3)-linked to a N-acetyl galactosamine (GalNac). CS is present on the cell surface and extracellular matrices of all connective tissues as protein complexes known as CS proteoglycans (CSPG). These molecules mediate various biological functions such as central nervous system development, signal transduction, morphogenesis, viral, and bacterial infections. Though CS oligosaccharides are involved in a range of biological functions, little is known about the optimum structures of the CS oligosaccharides responsible for biological activity. Thus far, CS from natural sources have been the most common way to obtain these oligosaccharides, but the heterogeneity and complexity of these oligosaccharides make the establishment of structure-activity studies (SAR) difficult. Therefore, the chemical synthesis of well-defined CS oligosaccharides libraries are necessary and will help elucidate the role of CS in biology as well as identify potential therapeutic applications. To address this deficiency, a modular approach was developed for the parallel combinatorial synthesis of CS oligosaccharides. In this approach, a small number of selectively protected disaccharide building blocks were easily converted into glycosyl donors and acceptors for the preparation of a wide range of oligosaccharides. Herein, we report the synthesis of heterogeneous tetra-, hexa-, and, octasaccharide CS standards based on motifs that have been shown to act as cell surface receptors for the parasite Plasmodium falciparum causing pregnant women to become susceptible to malaria despite previous immunity.