Synthesis and interaction with uridine phosphorylase of 5'-deoxy-4',5-difluorouridine, a new prodrug of 5-fluorouracil

Article abstract of DOI:10.1021/jm00401a008

5'-Deoxy-4',5-difluorouridine (4'-F-5'-dFUrd) (10) has been synthesized on the basis of the rationale that the labilization of the glycosidic linkage caused by the 4'-fluoro substituent might allow this compound to be a better prodrug form of the anticancer drug 5-fluorouracil (FUra) than is the widely studied fluoropyrimidine 5'-deoxy-5-fluorouridine (5'-dFUrd). The rate of solvolytic hydrolysis of the glycosidic linkage of 4'-F-5'-dFUrd at pH 1 was about 500-fold faster than that of 5'-dFUrd. Since uridine phosphorylase is thought to be the enzyme that causes degradation of 5'-dFUrd in vivo to generate FUra, we compared the substrate interactions of 5'-dFUrd and 4'-F-5'-dUrd with this enzyme. The V(max) for hydrolysis of 4'-F-5'-dFUrd to FUra by uridine phosphorylase was about 5-fold greater than that of 5'-dFUrd, whereas the K(m) value of 4'-F-5'-dFUrd was 10-fold lower. The combination of these two factors results in 4'-F-5'-dRUrd having a 50-fold higher value of V/K than does 5'-dFUrd. Against L1210 cells in culture, the IC₅₀ value for growth inhibition by 4'-F-5'-dFUrd was 3 x 10^-7 compared to 3 x 10^-6 for 5'-dFUrd.