Synthesis and biological activity of 5'-substituted 5-fluoropyrimidine nucleosides.

Abstract

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.