Abstract: Disclosed are 5?-substituted nucleoside monophosphates, which contain 5-fluorouracil or 5-fluorothiouracil as the nucleobase. In general, the 5?-substituted nucleoside monophosphates disclosed herein can inhibit human thymidylate synthase and thereby possess anti-cancer therapeutic effects. The 5?-substitution in these nucleoside monophosphates can prevent metabolic cleavage of the monophosphate group, mediated by enzymes such as 5?-nucleotidases, phospholipase D, etc. This feature can improve metabolic profiles, enhance target specificity, and/or reduce side effects of these compounds, compared to their corresponding unsubstituted analogs. Also disclosed are prodrugs of these 5?-substituted nucleoside monophosphates. After administration, the prodrugs can be metabolized to release their corresponding 5?-substituted nucleoside monophosphates. Methods of treating cancer using the 5?-substituted nucleoside monophosphates and prodrugs thereof are disclosed.

Abstract: Disclosed are acyclic nucleoside prodrugs with improved metabolic stability and oral bioavailability. In general, the prodrugs are derivatives of acyclic nucleoside phosphonates containing a lipid-like moiety that can increase oral absorption and subsequent stability in the liver and plasma. Preferably, the lipid-like moiety can resist enzyme-mediated ?-oxidation, such as ?-oxidation catalyzed by cytochrome P450 enzymes. Also disclosed are pharmaceutical formulations of the acyclic nucleoside prodrugs. The acyclic nucleoside prodrugs and pharmaceutical formulations thereof can be used to treat viral infections, such as HIV infections, and/or viral-associated cancer, such as HPV-associated cancers.