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

Caren L 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

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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Prodrugs
Fluorodeoxyuridylate
Bioactivity
Leukemia L1210
Cyclization
Cell proliferation
Growth
Thymidine
Inhibitory Concentration 50
Anions
Hydrolysis
Nucleotides
Cell Proliferation
Nuclear magnetic resonance
Ions
5-fluoro-2'-deoxyuridine
phosphoramidic acid

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological activity of novel 5-fluoro-2'-deoxyuridine phosphoramidate prodrugs. / Meyers, Caren L; Hong, L.; Joswig, C.; Borch, R. F.

In: Journal of Medicinal Chemistry, Vol. 43, No. 22, 02.11.2000, p. 4313-4318.

Research output: Contribution to journalArticle

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