Journal of Medicinal Chemistry p. 11 - 14 (1984)
Update date:2022-07-30
Topics:
Ajmera, Sudhir
Bapat, Ashok R.
Danenberg, Kathleen
Danenberg, Peter V.
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 (Ki = 1.7 mM). 3'-FFdUMP inhibits dTMP synthetase competitively with deoxyuridylate (Ki = 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 (konobsd = 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 (koffobsd = 1.4*10-2 min-1) similar to that of the potent inhibitor 5-fluoro-2'-deoxyuridilate (koffobsd = 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.
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