Synthesis and biological activity of 5-fluoro-2',3'-dideoxy-3'-fluorouridine and its 5'-phosphate

Publisher Website
Google Scholar
Abstract
5-Fluoro-2'',3''-dideoxy-3''-fluorouridine (3''-FFdUrd) and 5-fluoro-2'',3''-dideoxy-3''-fluorouridine 5''-phosphate (3''-FFdUMP) [potential cytotoxic drugs] were synthesized, and their interactions with thymidine (dThd) phosphorylase [from rat Lewis lung carcinoma] and thymidylate (dTMP) synthase [from Lactobacillus casei], respectively, were 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-methylenetetrahydrofolate, the inhibition increase with time in a 1st-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 (koffobsd = 1.4 .times. 10-2 min-1 similar to that of the potent inhibitor 5-fluoro-2''-deoxyuridylate (koffobsd = 1.3 .times. 10-2 min-1) from its ternary complex with dTMP synthetase. These results are explained in terms of a 2-stage model involving the initial formation of a reversible adsorption complex, followed by a slow conversion to a tight-binding catalytic complex. [3''-FFdUrd exhibited growth inhibition against L1210 mouse leukemia cells.].