Synthesis and biological activity of 5'-substituted 5-fluoropyrimidine nucleosides.
5'-Deoxy-5-fluorouridine (5'-dFUrd, 1) possesses a significantly higher chemotherapeutic index than other fluoropyrimidines as a result of its being selectivity cleaved in tumors to 5-fluorouracil (FUra) by uridine phosphorylase. Because 1 is a relatively poor substrate for this enzyme, we synthesized a series of 5'-deoxy-5'-substituted-5-fluorouridine (FUrd) derivatives in an effort to obtain compounds that might have improved substrate interactions compared to 1 and thus possibly be better prodrugs of FUra. Three derivatives, 5'-O-tosyl-FUrd (13), 5'-O-mesyl-FUrd (14), and 5'-deoxy-5'-bromo-FUrd (15), had cytostatic activity against L1210 and CCRF-CEM leukemic cells in culture superior to that of 1. In preliminary in vivo antitumor studies against L1210 leukemic cells in mice, 5'-deoxy-5'-chloro-FUrd (4), 5'-O-mesyl-FUrd (14), an 5'-deoxy-5'-fluoro-FUrd (18) gave percent increases in life span of 64, 58, and 58, respectively, compared to a value of 20 for compound 1.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D014529:Uridine