Synthesis and Biological Activity of 5-Fluoro-2',3'-dideoxy-3'-fluorouridine and Its 5'-Phosphate

Article abstract of DOI:10.1021/jm00367a003

5-Fluoro-2',3'-dideoxy-3'-fluorouridine (3'-FFdUrd) and 5-fluoro-2',3'-dideoxy-3'-fluorouridine 5'-phosphate (3'-FFdUMP) have been synthesized, and their interactions with thymidine (dThd) phosphorylase and thymidylate (dTMP) synthetase, respectively, have been examined. 3'-FFdUrd is not a substrate for dThd phosphorylase, but is a weak, noncompetitive inhibitor (K_i = 1.7 mM). 3'-FFdUMP inhibits dTMP synthetase competitively with deoxyuridylate (K_i = 0.13 mM) when both the substrate and inhibitor are present simultaneously.However, in the presence of 5,10-methylenete trahydrofolate, the inhibition increases with time in a first-order manner (k_on^obsd = 0.029 s^-1).A complex is formed between <6-3H>3'-FFdUMP and dTMP synthetase, which is isolable on nitrocellulose filters, and has a dissociation rate (k_off^obsd = 1.4*10^-2 min^-1) similar to that of the potent inhibitor 5-fluoro-2'-deoxyuridilate (k_off^obsd = 1.3*10^-2 min^-1) from its ternary complex with dTMP synthetase.These results are explained in terms of a two-stage model involving the initial formation of a revesible adsorption complex, followed by a slow conversion to a tight-binding catalytic complex.