New methods for the chemical synthesis of glycosaminoglycans
Dhamale, Omkar Prabhakar
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Glycosaminoglycans (GAGs) represent a major portion of proteoglycans which in turn are an integral part of the extracellular matrix surrounding mammalian cells. GAGs promote important biological functions as they participate in a wide range of physiological processes like metabolism, transport and regulation. Many of these interactions have been extensively studied and characterized, but the GAG motifs that mediate these important interactions have been seldom understood. The incapability to perform necessary structure-activity-relationship studies is due to the lack of novel synthetic technologies to access a library of well-defined GAG oligosaccharides. This difficulty can be attributed to the structural complexity associated with GAG which arises from an equally complex biosynthetic pathway. Significant members of the GAG family are heparin and heparan sulfate (HS) and dermatan sulfate (DS). Therefore, we have designed new techniques for the stereoselective synthesis of HS and DS oligosaccharides that employ a fairly small number of orthogonally protected building blocks, which can easily be converted into glycosyl donors and acceptors and utilized to construct respective GAG fragments. We have used a preglycosylation oxidation approach to address the issue of installation of uronic acids. A novel C2 ester participating functionality (pivaloyl acetate) was utilized for stereoselective 1,2-trans glycosidic linkages without compromising coupling efficiency. In the modular synthesis of DS, our strategic design allowed us to incorporate sulfates at all the required positions with absolute control and precision. We utilized orthogonal protecting groups for the construction of iduronic acid and galactosamine building blocks which allowed us to rapidly disassemble the derivatives to their final deprotected forms. We also attempted to construct large HS oligosaccharides fragments using a modular strategy by performing a rigourous study to achieve efficient stereoselective α-1,2 cis glycosidic coupling between glucosamine donor and GlcA acceptor using a non-participating azido functionality at the C2 position of the glucosamine donor. Thus, we have reported new chemical strategies for the synthetic construction of GAG motifs which will be helpful in addressing the problems associated with the poor reactivity profile of uronic acids. Using the discussed methodologies we set a premise for generating newer synthetic strategies for the construction of complex GAG oligosaccharides.