Sulfonyl-containing nucleoside phosphotriesters and phosphoramidates as novel anticancer prodrugs of 5-fluoro-2′-deoxyuridine 5′- monophosphate (FdUMP)

Yuan Wan Sun, Kun Ming Chen, Chul Hoon Kwon

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 β-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°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 μM) 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 prodruqs.

Original languageEnglish (US)
Pages (from-to)161-173
Number of pages13
JournalMolecular Pharmaceutics
Volume3
Issue number2
DOIs
StatePublished - Mar 1 2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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