Acyclic analogues of 5-fluoro-dUMP and 5-fluoro-2′-deoxyuridine: Synthesis and inhibition of thymidylate synthase and tumour cell growth

Krzysztof Felczak, Barbara Gołos, Jolanta M. Dzik, Wojciech Rode, Maria Bretner, David Shugar, Tadeusz Kulikowski

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

1-[(2-Hydroxyethoxy)methyl]-5-fluorouracil (HEMFU) and 1-[(1,3-dihydroxy-2-propoxy)methyl]-5-fluorouracil (DHPFU) were prepared by alkylation of the di-O-TMS derivative of 5-fluorouracil and phosphorylated with the use of the wheat shoot phosphotransferase system to their monophosphates, HEMFUMP and DHPFUMP. 1-(2-Phosphonyhnethoxyethyl)-5-fluorouracil (PMEFU) was obtained by condensation of diethyl-2-chloroethoxymethanephosphonate with 5-fluorouracil and cleavage of the alkylphosphoester with trimethylbromosilane. Inhibition of highly purified thymidylate synthase from mouse tumour Ehrlich carcinoma and leukemia L1210 cells by each of the nucleotide analogues, DHPFUMP, PMEFU and HEMFUMP, and of L5178Y mouse leukemia cell growth by the nucleoside (HEMFU) analogue, were studied. DHPFUMP proved to be the strongest inhibitor, non-competitive vs dUMP, with Kiapp 2.8μM for time-independent interaction with the enzyme and N5,N10-methylenetetrahydrofolate (CH2H4PteGlu). In the presence of CH2H4PteGlu, DHPFUMP exhibited time-dependent inactivation of the enzyme, the inactivation rate plots being biphasic and pointing to Ki values in the μM range (103-fold higher than for 5-fluoro-dUMP). HEMFUMP and PMEFU were much weaker inhibitors of the enzyme, with Kiapp values of 0.26 mM (non-competitive vs dUMP) and 30 mM (non-competitive vs dUMP), respectively. HEMFU, despite the weak interaction of its nucleotide analogue with the enzyme, proved to be a strong cell (L5178Y) growth inhibitor, with IC50 in the range 10-5 M.

Original languageEnglish (US)
Pages (from-to)75-82
Number of pages8
JournalActa Biochimica Polonica
Volume45
Issue number1
StatePublished - Dec 1 1998
Externally publishedYes

Keywords

  • Acyclic nucleoside phosphonates
  • Acyclic nucleosides
  • Acyclic nucleotides
  • Antitumor activity
  • Thymidylate synthase

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