Synthesis and interaction with uridine phosphorylase of 5'-deoxy-4',5-difluorouridine, a new prodrug of 5-fluorouracil.
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.
Ajmera
S
S
Department of Biochemistry, University of Southern California School of Medicine, Los Angeles 90033.
Bapat
A R
AR
Stephanian
E
E
Danenberg
P V
PV
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D005467:Floxuridine / Q000138:chemical synthesis* / Q000494:pharmacology / Q000031:analogs & derivatives; D005472:Fluorouracil / Q000378:metabolism*; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D008811:Mice, Inbred DBA; D010430:Pentosyltransferases / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014543:Uridine Phosphorylase / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D005467:Floxuridine; C056036:5'deoxy-4',5-difluorouridine; D010430:Pentosyltransferases; D014543:Uridine Phosphorylase; D005472:Fluorouracil