Synthesis, optimization and analysis of hexavalent sulfoglycodendrimers as anti-HIV agents

A study into the green optimization of the synthesis of 4 unique and novel sulfoglycodendrimers has been conducted. The ability of sulfoglycodendrimers to exhibit the multivalent effect makes them prime candidates for study. Multivalency plays a vital role in numerous interactions between proteins and receptors. In this research, a hexavalent dendrimer was created through a 5-step divergent pathway with both efficiency and purity in mind. The synthesized dendrimer core has been shown to have improved water solubility and stability compared to commercially available option, PAMAM. In subsequent, steps defined oligosaccharides were coupled to the core followed by sulfation, thus creating 4 unique fully glycosylated sulfoglycodendrimers. The synthesis was conducted using green techniques developed in-house which include elements such as using aqueous bases, low molar equivalents of reactants and the utilization of a CEM MARS 5 laboratory grade microwave whenever possible. Using these methods, the reaction yields increased compared to traditional reactions, waste production was minimized, and synthesis time for the glycodendrimers decreased. The confirmed sulfoglycodendrimers generated were analyzed for HIV-1 binding inhibition through an in-house ELISA assay, and live cell neutralization assays were performed by the Montefiori lab at Duke University. In addition, the Montefiori lab conducted cytotoxicity assays to analyze the toxicity of sulfoglycodendrimers generated. All four sulfoglycodendrimers generated showed no inhibition of HIV-1 viral binding. However, all four sulfoglycodendrimers had no cytotoxicity at pharmalogically relevant dosages. In order to analyze relative binding affinity, Microscale Thermophores was conducted with the help of Dr. Eggers at California State University San Jose State, showing weak monomolecular binding between the sulfoglycodendrimers and the viral protein of interest, gp120. It is believed the sulfoglycodendrimers generated do not have anti-viral activity due to a relative lack of flexibility within the dendrimer core for significant attachment strength. The insights gained from this project will guide future projects within the McReynolds lab and the field of sulfoglycodendrimers chemistry to make active anti-viral compounds.