Chemical synthesis of 4’-modified nucleoside analogues

Nucleosides are the building blocks of DNA and RNA. Due to their involvement in a myriad of biological processes, nucleoside analogues represent an ideal starting point for the discovery of new drug candidates and have formed a cornerstone of treatment for viral infections and cancers. Notwithstanding their rich history in successful drug development, therapeutic intervention using nucleoside analogues is often limited by poor cellular uptake, low conversion to the active triphosphate metabolite, rapid degradation or clearance and development of resistance profiles in certain cell types. Consequently, research activity in this field continues to develop syntheses for next generations of biologically active nucleoside analogues that can overcome these limitations and provide new therapeutic options. Within this context, 4’-postion modification of the ribose ring represents an important structural motif for exploration. We have developed synthetic methods to chemcially synthesise 4’-thionucleosides, alongside replacing the furanosyl oxygen with CHF and CF₂ groups.