Regioselective Synthesis of Glycosaminoglycan Analogs

Glycosaminoglycans (GAGs), a large family of complex, unbranched polysaccharides, display a variety of essential physiological functions. The structural complexity of GAGs greatly impedes their availability, thus making it difficult to understand the biological roles of GAGs and structure-property relationships. A method that can access GAGs and their analogs with defined structure at relatively large scales will facilitate our understandings of GAG biological roles and biosynthesis modulation.

Cellulose is an abundant and renewable natural polymer. Applications of cellulose and cellulose derivatives have drawn increasing attention in recent decades. Chemical modification is an efficient method to append new functionalities to the cellulose backbones. This dissertation describes chemical modification of cellulose and cellulose derivatives to prepare unsulfated and sulfated GAG analogs. Through these studies, we have also discovered novel chemical reactions to modify cellulose. Systematic study of these novel chemistries is also included in this dissertation.

We first demonstrated our preparation of two unsulfated GAG analogs by chemical modification of a commercially available cellulose ester. Cellulose acetate was first brominated, followed by azide displacement to introduce azides as the GAG amine precursors. The resulting 6-N3 cellulose acetate was then saponified to liberate 6-OH groups, followed by subsequent (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the liberated primary hydroxyl groups to carboxyl groups. Finally, the azides were reduced to amines using a novel reducing reagent, dithiothreitol (DTT). Alternatively, another process utilized thioacetic acid to reduce azides to a mixture of amine and acetamido groups.

Through pursuing these GAG analogs, we applied novel azide reductions by DTT and thioacetic acid that are new to polysaccharide chemistry. We systematically investigated the scope of DTT and thioacetic acid azide reduction chemistry under different conditions, substrates, and functional group tolerance. Selective chlorination is another interesting reaction we discovered in functionalization of cellulose esters. We applied this chlorination reaction to hydroxyethyl cellulose (HEC). We then utilized the chlorinated HEC as a substrate for displacement reactions with different types of model nucleophiles to demonstrate the scope of its utility.

Overall, we have designed a novel synthetic route to two unsulfated GAG analogs by chemical modification of cellulose acetate. Through exploration of GAG analogs synthesis, we discovered novel methods to modify polysaccharide and polysaccharide derivatives, including azide reduction chemistry and selective chlorination reactions. Successful synthesis of various types of GAG analogs will have great potential biomedical applications and facilitate structure-activity relationship studies.