Synthesis, physicochemical properties, and cytotoxicity of a series of 5'-ester prodrugs of 5-iodo-2'-deoxyuridine

Five aliphatic 5'-esters of 5-iodo-2'deoxyuridine (IDU) were synthesized via an acid chloride alcoholysis reaction. The solubility in pH 7.4 phosphate buffer, lipophilicity as determined by partition experiments in octanol/pH 7.4 buffer, and cytotoxicity of these potential prodrugs were evaluated. The esters showed a 43- to 250-fold increase in lipophilicity and a 1.6- to 14-fold decrease in aqueous solubility relative to IDU. At a concentration of 50 microM, all esters showed reduced cytotoxicity toward uninfected Vero cells relative to IDU.