Synthesis and characterization of glucose- and galactose- derived poly-amido-saccharides (PAS)
Chin, Stacy Lee
MetadataShow full item record
Polysaccharides are widely diverse in structure and can vary in molecular weight, sugar composition, monomeric sequence, stereochemistry, glycosidic linkage, branching, and functionalization. Due to these attributes, polysaccharides are highly abundant in nature and are found in a variety of applications across biology, chemistry, medicine, and commercial products. As the structural diversity within carbohydrate polymers is challenging to replicate under synthetic means, these materials are commonly isolated from natural resources, which introduces unwanted variation between batch samples and requires extensive purification to isolate final products. Although enzymatic approaches to obtain polysaccharides have been explored, these routes typically require expensive starting materials and cannot introduce non-natural functional groups. While chemical synthetic routes of polysaccharide structures and polymer-mimics have been reported, it is challenging to have synthetic control over molecular weight, stereochemistry, and linkages while maintaining the high density of similar functional groups and rigid pyranose backbone. Poly-amido-saccharides (PASs) are enantiopure carbohydrate polymers in which sugar units are joined by 1,2-amide linkages. By using an anionic ring-opening polymerization of β-lactam monomers, PAS structures are synthesized with control over molecular weight, functional groups, batch-to-batch consistency, and at low polydispersity. Importantly, PAS samples are water-soluble and contain the rigid pyranose backbone as found in natural polysaccharides. As PAS structures are not found in nature, the unnatural peptide linkage between monosaccharide units contributes to their unique structural features and chemical properties. The Grinstaff group has reported PASs to have a robust helical secondary structure; minimal cytotoxicity in different mammalian cell lines; ability to be functionalized on the monomer and polymer level; varying water-solubility depending on its sugar composition; and, potential to be recognized as natural carbohydrates (glucose-derived PAS are recognized by lectin concanavalin A similarly to glucose). Experimental and computational techniques, including circular dichroism, 2D-NMR spectroscopy, and molecular dynamics simulations, were used to explore structure-function relationships between glucose- (glc-) and galactose- (gal-) PAS structures. Cytotoxicity and cellular uptake studies were conducted to investigate their biocompatibility properties. Finally, sulfated glc-PASs structures were explored to possess anticoagulation activity and binding interactions with antithrombin III to serve as heparin-mimics to address current clinical challenges associated with heparin usage.