Inhibition of nucleoside phosphorylase cleavage of 5-fluoro-2'-deoxyuridine by 2,4- pyrimidinedione derivatives

Abstract

Several 2,4-pyrimidinedione (uracil) derivatives were evaluated as inhibitors of the pyrimidine nucleoside phosphorylases that cleave 5-fluorn-2'-deoxyuridine (FUdR) to 5-fluorouracil. Pyrimidinediones substituted at either N-1 or C-5, or both, markedly inhibited the phosphorolysis of FUdR by the uridine-deoxyuridine phosphorylases of Ehrlich ascites and Novikoff hepatoma cells. The most potent inhibitors were 5-benzyluracil derivatives substituted with alkoxy groups on the meta-position of the benzyl moiety; the most active of these was 5-{[3-(phenylmethoxy)phenyl]methyl}uracil. The same derivatives, however, did not inhibit the phosphorolysis of FUdR by the thymidine phosphorylases of murine liver, human leukocytes and HeLa (S3) cells. 6-Anilino and 6-(1-naphthylmethylamino) derivatives of uracil, which have been shown by others to inhibit the cleavage of FUdR by the thymidine phosphorylase activity of Escherichia coli, did not inhibit any of the mammalian thymidine or uridinedeoxyuridine phosphorylase activities. By contrast, pyrimidinediones substituted with smaller, non-hydrophobic groups at either C-5 or C-6, or both, inhibited the cleavage of FUdR by both the mammalian thymidine and uridine-deoxyuridine phosphorylases. The most active of these, 6-aminothymine, was also the best inhibitor of thymidine phosphorylase. Our results demonstrate differences in the active sites of the various pyrimidine nucleoside phosphorylases, and should provide a basis for the design of more potent and specific inhibitors of the nucleoside phosphorylase(s) responsible for the cleavage of FUdR in man.