Synthesis and application of specifically sulfated carbohydrates containing methacrylate functionality

Abstract

Polymeric materials containing sugar moieties have proven to be important biomaterials. Hydrophobic polymers based on methyl methacrylate as well as hydrophilic polymers based on polysaccharides have been used as matrix-forming materials for tablets. A number of procedures for preparation of polysulfated carbohydrate derivatives have been published in literature1-3. However, there are no reports of mono- or disulfated methyl methacrylate derivatives of carbohydrates. The major focus of this thesis is synthesis and characterization of novel polymerizable methacrylate derivatives of mono- and disulfated carbohydrates. The position of sulfate group(s) as well as methyl methacrylate functionality is varied among monomers such that upon polymerization, well defined sulfated carbohydrate containing polymers are produced. This will facilitate advances in the development of structure-activity relationships between sulfated carbohydrate polymers and their diverse biological activities. A second area of this thesis is investigation of the potential for these novel sulfated polymers to act as biomimics of natural sulfated polysaccharides (e.g. heparan sulfate). We have studied the bacterial internalization of Staphylococcus aureus with a number of sulfated polymers. We have also investigated the effect of the degree of sulfation of these polymers upon their interactions with bacteria such as Staphylococcus biological activities. A second area of this thesis is investigation of the potential for these novel sulfated polymers to act as biomimics of natural sulfated polysaccharides (e.g. heparan sulfate). We have studied the bacterial internalization of Staphylococcus aureus with a number of sulfated polymers. We have also investigated the effect of the degree of sulfation of these polymers upon their interactions with bacteria such as Staphylococcus biological activities. A second area of this thesis is investigation of the potential for these novel sulfated polymers to act as biomimics of natural sulfated polysaccharides (e.g. heparan sulfate). We have studied the bacterial internalization of Staphylococcus aureus with a number of sulfated polymers. We have also investigated the effect of the degree of sulfation of these polymers upon their interactions with bacteria such as Staphylococcus aureus Computer modeling has been recognized as a sophisticated tool to investigate the interactions of ligands and proteins. This led us to another direction taken by this research project to use computational techniques to determine possible interactions of our final sulfated polymers with heparin binding proteins (HBPs) such as fibroblast growth factor (FGF). We used molecular docking as well as molecular dynamic simulation to predict binding ability of our final polymers with HBPs and provide a detailed description of these systems at the molecular level. In an endeavor to improve the chemical and biological properties of our final polymers, we used a number of techniques such as surface grafting. Surface polymerization of our reactive carbohydrate monomers on some chemically activated surfaces such as polystyrene and glass was accomplished to enhance the hydrophilic interactions including attachment of hydrogels, immobilization of enzymes, or attraction of certain types of bacteria. Thus, multi-faceted synthetic, computational, and biological studies that are proposed in this thesis should find wide utility for development of novel glycopolymers for biomedical applications including drug delivery.