A series of sulfonyl-containing 5-fluoro-2'-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent beta-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33-12.23 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 degrees C. Acceleration of the elimination was observed in the presence of human plasma. Compounds with an FdUMP moiety (4-9) were considerably more potent than those without (1-3) as well as 5-fluorouracil (5-FU) against Chinese hamster lung fibroblasts (V-79 cells) in vitro. Addition of thymidine (10 microM) reversed the growth inhibition activities of only 5-FU and the compounds with an FdUMP moiety, but had no effect on those without. These results are consistent with thymidylate synthase as the target of the prodrugs.
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