Mechanism-based inactivation of thymidylate synthase by 5-(3-fluoropropyn-1-yl)-2'-deoxyuridine 5'-phosphate.
5-Fluoropropynyl-2'-deoxyuridine 5'-phosphate (3) was designed as a mechanism-based inactivator of thymidylate synthase (TS). The inhibitor was synthesized from 5-iodo-2'-deoxyuridine and propargyl alcohol by palladium-catalyzed coupling, followed by fluorination and selective phosphorylation. Incubation of TS with 3, in the presence or absence of the CH2H4folate cofactor, caused rapid, irreversible inactivation of the enzyme.
Kalman
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Department of Medicinal Chemistry, State University of New York at Buffalo, 14260, USA.
Nie
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Kamat
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D001667:Binding, Competitive; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D003956:Dialysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
C407728:5-(3-fluoropropyn-1-yl)-2'-deoxyuridine 5'-phosphate; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; C056075:iododeoxyuridylate; D013940:Thymidylate Synthase