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

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• 作者：Przemysł ; aw Ziemkowski ; Krzysztof Felczak ; Jarosł ; aw Poznań ; ski ; Tadeusz Kulikowski ; Zbigniew Zieliń ; ski ; Joanna Cieś ; la ; Wojciech Rode
• 关键词：Thymidylate synthase ; 2′ ; -Fluoro-substituted dUMP analogues ; NMR
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2007
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：12 October 2007
• 卷：362
• 期：1
• 页码：37-43
• 文件大小：226 K

摘要

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 J_HF 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.