Novel synthetic pathways for the preparation ofProTides as potential therapeutic agents

The phosphoroamidate (ProTide) approach is a prodrug technology aimed to circumvent metabolic bottlenecks in the activation of nucleoside-based drugs and optimise their intracellular delivery. The tremendous importance of the ProTide approach is highlighted by the approval of Sofosbuvir (Sovaldi®, HCV infections) and tenofovir alafenamide fumarate (TAF, Vemlidy®, HIV and HBV infections). A great deal of success is also demonstrated by many other compounds adopting this technology either in clinical trials or preclinical evaluations as antiviral and anticancer agents. Given the great impact of phosphor(n)oamidate nucleoside prodrugs in the antiviral arena and beyond, the application of this technology has grown dramatically. Several procedures are present in the literature for the preparation of phosphoroamidate prodrugs of nucleosides. However, an efficient and inexpensive diastereoselective synthesis to prepare ProTides as single diastereoisomers is missing. Additionally, the phosphonoamidate cognate class, one of the most significant groups of antiviral drugs, presents many synthetic challenges. Recent literature reported the synthesis of novel acyclic nucleoside backbones including the phosphonate derivatives bearing a double bond in the aliphatic chain. However, the methodologies described for the preparation of ProTides on alkenyl acyclic nucleosides are scarce and inefficient. Beside phosphoroamidates and phosphonoamidates, many difficulties can also be encountered in the preparation of modified unnatural nucleosides and related prodrugs. One of them is the ProTide of 2’-deoxy-O6-methylguanosine to be tested for mitochondrial DNA depletion syndrome. In this context, the research discussed in this thesis is focused on addressing the synthetic problems related to unnatural nucleosides and their ProTides. This thesis aims to explore novel methodologies for the preparation of both phosphoroamidate and phosphonoamidate prodrugs of biologically relevant nucleosides in order to give easy access to novel ProTides to be evaluated for their potential therapeutic acti