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, a series of 5''-deoxy-5''-substituted-5-fluorouridine (FUrd) derivatives was synthesized 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 [mouse] and CCRF-CEM [human T-lymphoblastoid] 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), and 5''-deoxy-5''-fluoro-FUrd (18) gave increases in life span of 64, 58 and 58%, respectively, compared to 20% for compound 1.