Interactions of 2′-fluoro-substituted dUMP analogues with thymidylate synthase

Przemysław Ziemkowski, Krzysztof Felczak, Jarosław Poznański, Tadeusz Kulikowski, Zbigniew Zieliński, Joanna Cieśla, Wojciech Rode

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

A series of 2′-fluoro-substituted dUMP/FdUMP analogues were synthesized, their interaction with human recombinant thymidylate synthase investigated, and structural 1H and 19F NMR study of the corresponding nucleosides performed. While 2′-F-dUMP (fluorine in the "down" configuration), in striking contrast to 2′-F-ara-UMP (fluorine in the "up" configuration) and 2′,2′′-diF-dUMP, showed substrate activity, 2′-F-ara-UMP and 2′,2′′-diF-dUMP were classic inhibitors, and 2′,5-diF-ara-UMP behaved as a strong slow-binding inhibitor, suggesting the 2′-F substituent in the "up" position to interfere with the active center cysteine thiol addition to the pyrimidine C(6) and the pyrimidine C(5)-F to prevent this interference. In support, the direct through space heteronuclear coupling JHF was observed for the fluorine "up" derivatives, 2′-F-ara-U and 2′,5-diF-ara-U, causing the splitting of the H(6) resonance lines. The absence of such splitting in 2′,2′′-diF-dUrd, indicating an unusual orientation of the base in relation to the furanose, was associated with an exceptionally weak interaction with the enzyme.

Original languageEnglish (US)
Pages (from-to)37-43
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume362
Issue number1
DOIs
StatePublished - Oct 12 2007
Externally publishedYes

Keywords

  • 2′-Fluoro-substituted dUMP analogues
  • NMR
  • Thymidylate synthase

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