Interactions of 2′-fluoro-substituted dUMP analogues with thymidylate synthase
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 con...
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Veröffentlicht in: | Biochemical and biophysical research communications 2007-10, Vol.362 (1), p.37-43 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0006-291X 1090-2104 |
DOI: | 10.1016/j.bbrc.2007.07.097 |