Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'-phosphate

Abstract

5-Fluoro-5''-(2-oxo-1,3,2-oxazaphosphorinan-2-yl)-2''-deoxyuridine (1a) and 5-fluoro-5''-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2''-deoxyuridine (1b) were prepared by reaction of 5-fluoro-2''-deoxyuridine (7a) and phosphoryl chloride with 3-amino-1-propanol and 1,3-propanediol, respectively. The thymidine analogs 1c [5''-(2-oxo-1,3,2-oxazaphosphorinan-2-yl)thymidine] and 1 d [5''-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)thymidine] were prepared similarly from thymidine. Compounds 1a-d were resistant to degradation by 5''-nucleotidase, alkaline phosphatase, venom phosphodiesterase and crude snake venom. None of these compounds were significantly biotransformed when incubated with mouse hepatic microsomal preparations in the presence of an NADPH-generating system. When administered i.p. for 5 consecutive days, 1a was nearly as effective as 5-fluorouracil at prolonging the life-spans of BDF1 mice implanted i.p. with leukemia P-388. Much larger dosages of 1a were required for optimal activity. Compound 1b administered similarly was only marginally effective. Neither 1a nor 1b was active against a P-388 mutant resistant to 5-fluorouracil.