Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside

J Med Chem. 2011 Oct 27;54(20):7247-58. doi: 10.1021/jm200815w. Epub 2011 Sep 27.


The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Equilibrative Nucleoside Transporter 1 / genetics
  • Floxuridine / analogs & derivatives*
  • Floxuridine / chemical synthesis*
  • Floxuridine / pharmacology
  • Humans
  • Mycoplasma hyorhinis / enzymology
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Pyrimidine Phosphorylases / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Equilibrative Nucleoside Transporter 1
  • Organophosphorus Compounds
  • Prodrugs
  • SLC29A1 protein, human
  • Floxuridine
  • Pyrimidine Phosphorylases