Synthesis of neuraminidase inhibitors and bioactive polymers

Neuraminidases are a group of enzymes involved in the cleavage of the terminal neuraminic acid (Neu5Ac) attached to glycoproteins and glycolipids. This process is necessary for adhesion recognition, and infection of viruses and other pathogens. Neuraminidase plays an essential role in influenza virus infection. Design and synthesis of neuraminidase inhibitors would be an exciting approach, which may lead to anti-virus, anti-bacteria and anticancer agents.; In our studies, a samarium diiodide reagent was used to synthesize neuraminic acid based α-C-glycosides. These C-glycosides, which are enzymatically stable and mimic enzyme substrates, were tested for their inhibitory activity towards bacterial neuraminidase. Some C -glycosides were found to be potent inhibitors (K_i 16–30 μM) of this neuraminidase. Further studies were carried out in combinatorial synthesis of neuraminic acid containing C-glycosides. Combinatorial synthesis is an attractive approach to synthesize a large set of structurally related compounds in a short period of time. A methodology for synthesizing neuraminic acid based C-glycosides in solution phase as well as solid support was developed. Using chemoenzymatic approaches, C-glycoside was obtained on derivatized glass beads.; Preparation of homogenous and structurally defined polysaccharide analogs have a wide range of applications as coating agents, for molecular recognition in biomedical materials, and for use in biotechnology. The polyvalency inherent in carbohydrate-based polymers is an important feature, which allows these materials to serve as cell surface mimics leading to an improved understanding of carbohydrate-protein interactions. Chemoenzymatic routes are developed to obtain a series of nucleotide-based phenolic polymers and their abilities as affinity matrixes were examined. In addition, chemical and chemoenzymatic syntheses of three mucin analogs were undertaken. In these studies, phenolic mucin C-glycoside polymers showed high inhibitory effect toward neuraminidase compared with simple C-glycosides, indicating that multivalency can markedly enhance ligand interaction and potentially increase the biological effects. These neuraminic acid rich macromolecules, capable of tight multivalent interactions with proteins, might be useful as drug candidates or in the preparation of surfaces protecting barrier against pathogen infection.