Synthesis and biological activity of novel 5-fluoro-2'-deoxyuridine phosphoramidate prodrugs

C. L. Freel Meyers, L. Hong, C. Joswig, R. F. Borch

Research output: Contribution to journalArticle

Abstract

A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 μM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. 31P NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.

Original languageEnglish (US)
Pages (from-to)4313-4318
Number of pages6
JournalJournal of medicinal chemistry
Volume43
Issue number22
DOIs
StatePublished - Nov 2 2000
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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