Stereoselective synthesis of fluorinated glycoconjugates.Tuning physicochemical parameters for therapeutic drug development

Identifier:  TDX:4027

Handle: https://hdl.handle.net/20.500.11797/TDX4027

Authors:  Bascuas Jiménez de Bagúes, Isabel

Abstract:
Glycans play important roles in a variety of biological processes, such as adhesion, immunity, inflammation, hostpathogen interactions, and cancer metathesis. However, native glycan structures have shown little success as therapeutics due to their poor pharmacokinetic properties. Fluorinated glycomimetics have shown to be an incredibly useful tool in the development of new drugs, since fluorine substitution can be used to improve activity, bioavailability and the glycosyl bond stability. Despite their prevalence, the stereoselective synthesis of fluorinated glycosides remains one of the most challenging areas of organic chemistry. In this context, this PhD dissertation aims at developing new synthetic methodologies for the stereoselective preparation of 2-deoxy-2-fluoro glycosides and previously uncharted 2-deoxy-2-trifluoromethyl glycosides. The study of their key physicochemical properties revealed desired pharmacokinetic changes for fluorinated and trifluoromethylated glycosides, such as improved lipophilicity and increased glycosidic bond stability. Moreover, fluorinated and trifluoromethylated glycosides maintain the conformation of their native strcutures, demonstrating that they could act as excellent bioisosteres of their native congeners. Finally, the described methodologies were applied for the stereoselective synthesis of biologically relevant fluorinated glycosyl derivates.