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. / Doctor of Philosophy / Polysaccharides are long chains of natural sugars. Glycosaminoglycans (GAGs) are an important class of polysaccharides which have complicated chemical structures and play critical roles in many biological processes, including regulation of cell growth, promotion of cell adhesion, anticoagulation, and wound repair. Current methods to obtain these GAGs and GAG analogs are expensive, lengthy, and limited in capability. Novel methods to access these GAGs and their analogs would be promising and would facilitate understanding of biological activities of GAGs. Cellulose is an abundant polymer on earth and provides structural reinforcement in plant cell walls. Cellulose can be further chemically modified to tailor its physiochemical properties. Cellulose and cellulose derivatives have been widely used in many industries for various applications, such as textiles, plastic films, automotive coatings, and drug formulation. This dissertation focuses on modifying inexpensive, abundant cellulose and its derivatives to GAGs and GAG analogs. We start from the simple plant polysaccharide cellulose and obtain structurally complicated analogs of animal-sourced GAGs and GAG analogs. We reached our goal by designing a carefully crafted synthetic route, finally successfully obtaining two types of novel GAG analogs. During this process, we discovered two useful chemical reactions. We systematically investigated these chemical reactions and demonstrated their utility for polysaccharide chemical modification. These successful chemical syntheses of GAGs and their analogs will accelerate our understanding of their natural functions and have potential biomedical applications. The novel chemical methods we discovered will be helpful in chemical modification of polysaccharides.

Polysaccharides are one of the most abundant and diverse families of natural polymers, and have an incredibly wide range of natural functions including structural reinforcement, energy storage, aqueous rheology modification, and communication and identity. Application of native polysaccharides like cellulose as sustainable materials is limited by some inherent drawbacks such as insolubility in common solvents including water, and poor dimensional stability. To increase their functionality and utility, researchers have sought to tailor the chemical and physical properties of cellulose and other polysaccharides using a variety of chemical modification techniques, resulting in a number of important, useful commercial derivatives. Because of their greater biocompatibility and biodegradability, and low immunogenicity, naturally derived cationic polymers including cationic polysaccharide derivatives are very attractive candidates for biomedical applications, due to the fact that they are capable of binding with anionic biomolecules, such as nucleic acids and certain proteins, via electrostatic interactions. However, there are relatively few practical synthetic methods reported for their preparation. We demonstrated a useful and efficient strategy for cationic polysaccharide salt preparation by reaction of 6-bromo-6-deoxypolysaccharides such as 6-bromo-6-deoxycellulose esters with pyridine or 1-methylimidazole exclusively at the C-6 position, resulting in high degrees of substitution (DSs). These permanently cationic polysaccharide derivatives have been demonstrated to dissolve readily in water, and bind strongly with a hydrophilic and anionic surface. Availability of these cationic polysaccharides will facilitate structure-property relationship studies for biomedical uses including drug delivery and bioelectronics applications. We also extended the chemistry, reacting 6-imidazolo-6-deoxycellulose with propane sultone, leading to a new synthetic pathway to zwitterionic cellulose derivatives. In addition to cationic and zwitterionic derivatives, we found a simple, efficient route to carboxyl-containing polysaccharide derivatives from curdlan esters via regioselective ring-opening reactions catalyzed by triphenylphosphine (Ph3P) under mild conditions. Curdlan, a polysaccharide used by the food industry and in biomedical applications, was employed as starting material for preparing these carboxyl-containing derivatives by a reaction sequence of bromination, azide displacement and ring-opening reaction with cyclic anhydrides, affording high conversions. These modification techniques have been demonstrated to display essentially complete regio- and chemo-selectivity at C-6. These novel polysaccharide-based materials starting from abundant and inexpensive curdlan are promising for some applications such as amorphous solid dispersion (ASD) oral drug delivery. / Ph. D. / Polysaccharides are chains of natural sugars. They constitute one of the most abundant and diverse families of natural polymers (polymers are chains of small molecules, and polysaccharides are a class of polymers), and in nature polysaccharides play an incredibly wide range of functions such as structural reinforcement, energy storage, changing the viscosity of solutions of things in water, and communication. Cellulose, a polymer comprising long chains of linked glucose molecules, may be the most abundant natural polysaccharide on earth. Application of native cellulose as a sustainable material is limited by its inability to dissolve in water or commonly used organic solvents, poor dimensional stability, inability to melt and flow when heated, and the fact that it degrades when exposed to the environment. In order to increase its functionality and utility, a number of research groups have tried to tailor the chemical and physical properties of things made from cellulose (cellulose “derivatives”) using various chemical modification techniques, resulting in some important, useful commercial cellulose derivatives. The Edgar group, in the recent years has developed a series of new techniques to synthesize various cellulose derivatives for effective oral drug delivery. We have demonstrated that these cellulose derivatives are capable of preventing drugs from forming insoluble crystals, meanwhile protecting the drugs from the harsh environment of the stomach. As a result, these formulations based on cellulose derivatives enhance the solubility of drugs in the digestive tract, and the ability of the drug to permeate to the blood stream, thereby enhance distribution to the parts of the body where it is needed, is enhanced as well. Cellulose- and other polysaccharide-based polyelectrolytes are very attractive candidates for biomedical and therapeutical applications. However, currently, the set of commercially available cellulose derivatives is limited in number and diversity, and contains no positively charged derivatives. This dissertation focuses on the development of new ways to make charged polysaccharide derivatives using chemical modification of cellulose, cellulose esters, and other polysaccharides. Unlike conventional methods which require harsh reaction conditions or metal catalysts, the new approaches in this dissertation offer simple and efficient ways to make a wide variety of charged derivatives of cellulose or other polysaccharides under mild conditions. Availability of these polysaccharide-based charged polymers will help us design more useful, economical materials for biomedical, pharmaceutical, and other applications including gene or drug delivery, oral delivery of potent and selective protein drugs, agricultural applications, and coatings.