Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'-phosphate.
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 analogues, 1c and 1d, were prepared similarly from thymidine. Compound 1b was synthesized in better yield from 13a and trimethylene phosphate with triphenylphosphine/diethyl azodicarboxylate as a condensing agent. 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 intraperitoneally (ip) for 5 consecutive days, 1a was nearly as effective as 5-fluorouracil at prolonging the life spans of BDF1 mice implanted intraperitoneally with leukemia P-388. However, 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.
D015720:5'-Nucleotidase; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001088:Arabinonucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis*; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009708:Nucleotidases / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism
D001088:Arabinonucleotides; D003856:Deoxyuracil Nucleotides; D005468:Fluorodeoxyuridylate; D009249:NADP; C038724:2',5-difluoro-1-arabinosyluridine monophosphate; D009708:Nucleotidases; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; D010727:Phosphoric Diester Hydrolases; D005472:Fluorouracil