Novel Synthetic Routes for the synthesis of Active Nucleotide Pharmaceutical Ingredients

Abstract

Glycosides are an important class of naturally occurring carbohydrate compounds that have immense significance in the genetic makeover of the body. Chemically, glycosides are often defined as compounds where carbohydrate molecules are covalently linked to an aglycone via a glycosidic bond. Glycosides can be linked by variety of glycosidic bonds leading to different classes of glycosides. N-glycosides or Glucosamines are glycosides where the anomeric linkage is a C-N linkage. Among other naturally occurring N-glycosides, nucleosides are the most relevant and commonly known N-glycosides since they are the fundamental building blocks of DNA and RNA. Besides, they play a key role in various other key cellular processes. This has led scientists to target this class of compounds to chemically modify and synthesize drugs that can mimic their physiological counterparts and exploit their mechanism to introduce therapeutic benefits. Substituted nucleoside analogues are hence seen as the key in medicinal chemistry for pioneering antiviral and anticancer therapies. Chemical synthesis and modification of nucleosides though has remained a challenging process owing to compatibility issues between basicity of nucleobases and acidic reaction protocols. Thus, novel strategies for successfully synthesizing nucleosides are a constantly evolving and challenging endeavour keeping all the limitations in mind. In this project, I have aimed to synthesize two furanose nucleoside derivatives with different C-2’ substituents in sugar moiety utilizing different protecting groups through a novel synthetic route developed by our group while working on N-glycosides. For this process, I have used adenine as the nucleobase acceptor and ribose sugar moiety as the donor. N-glycosylation was achieved through [Au/Ag] catalysis of the acceptor and ethynyl cyclohexyl carbonate ribose donor which had been previously established by the Hotha group. Various post glycosylation modifications were tried at the C-2’ position of the sugar moiety to create a library of modified nucleoside analogues that could be further developed to examine therapeutic benefits. In a nutshell, an efficient and stable synthetic procedure to develop various modified nucleosides from furanose has been envisioned in this project.