Ajmera S, Bapat A R, Stephanian E, Danenberg P V
Department of Biochemistry, University of Southern California School of Medicine, Los Angeles 90033.
J Med Chem. 1988 Jun;31(6):1094-8. 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 Vmax for hydrolysis of 4'-F-5'-dFUrd to FUra by uridine phosphorylase was about 5-fold greater than that of 5'-dFUrd, whereas the Km value of 4'-F-5'-dFUrd was 10-fold lower. The combination of these two factors results in 4'-F-5'-dFUrd 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.
5'-脱氧-4',5-二氟尿苷（4'-F-5'-dFUrd）（10）的合成基于这样的理论依据：4'-氟取代基引起的糖苷键不稳定可能使该化合物成为比广泛研究的氟嘧啶5'-脱氧-5-氟尿苷（5'-dFUrd）更好的抗癌药物5-氟尿嘧啶（FUra）的前药形式。4'-F-5'-dFUrd糖苷键在pH 1时的溶剂解水解速率比5'-dFUrd快约500倍。由于尿苷磷酸化酶被认为是体内导致5'-dFUrd降解生成FUra的酶，我们比较了5'-dFUrd和4'-F-5'-dUrd与该酶的底物相互作用。尿苷磷酸化酶将4'-F-5'-dFUrd水解为FUra的Vmax约比5'-dFUrd大5倍，而4'-F-5'-dFUrd的Km值低10倍。这两个因素的结合导致4'-F-5'-dFUrd的V/K值比5'-dFUrd高50倍。在培养的L1210细胞中，4'-F-5'-dFUrd生长抑制的IC50值为3×10^(-7)，而5'-dFUrd为3×10^(-6)。
