Synthesis and Evaluation of DPA Analogs as Substrates for Arabinofuranosyltransferases

Abstract

Mycobacteria have a complex and robust cell wall that is important for its survival. Two major components of the cell wall are arabinogalactan (AG) and lipoarabinomannan (LAM). Both AG and LAM contain an arabinan domain, which is composed of arabinofuranose (Araf) residues. Decaprenylphosphoryl-beta-D-arabinofuranose (DPA) serves as the only Araf donor and is used by mycobacteria to assemble the arabinan domain. This process is catalyzed by a group of enzymes termed arabinofuranosyltransferases (AraTs), which have been identified as potential drug targets. To investigate the biosynthetic pathway of the arabinan, scientists have used chemical methods to synthesize DPA and analogs, including (Z,Z)-farnesylphosphoryl-beta-D-arabinofuranose (FPA), which is a known substrate for AraTs. In this thesis, the first investigation focuses on synthesizing six derivatives of FPA, in which different hydroxyl groups are replaced with either a fluorine atom or an azido group. The synthesis of these target molecules was achieved from their corresponding thioglycoside building blocks, which were converted into glycosyl bromides before being phosphorylated. Deprotection of the glycosyl phosphates, followed by the coupling with (Z,Z)-farnesol and the final deprotection afforded the target compounds. The second investigation centers on the evaluation of these DPA analogs as substrates for AraTs using an in vitro cell-free assay. Although the six target molecules have not been tested, I describe the evaluation of the known compound FPA as a substrate for AraTs.