Synthesis and antitumor activity of an acyclonucleoside derivative of 5-fluorouracil

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Abstract
The pyrimidine acyclonucleoside 5-fluoro-1-[(2-hydroxyethoxy)methyl]uracil (3) was synthesized as part of a program aimed at the development of new 5-fluorouracil derivatives with fewer side effects and a broader margin of safety. Condensation of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine with 2-acetoxyethyl acetoxymethyl ether in the presence of SnCl4 afforded the acetate ester, which on deprotection with NaOMe gave 3 in 50-60% overall yield. The 5-bromo and 5-iodo analogues were obtained similarly. Reaction of 5-fluoro-4-(methylthio)-2-[(trimethylsilyl)oxy]pyrimidine with 2-acetoxyethyl acetoxymethyl ether and SnCl4, followed by ammonolysis, yielded 5-fluoro-1-[(2-hydroxyethoxy)methyl]cytosine (12). Deamination of 12 with nitrous acid produced 3, thereby confirming that alkylation of 5-fluoro-2,4-bis[(trimethylsilyl)oxy]pyrimidine had occurred at N1. The ID50 [median inhibitory dose] of 3 against L1210 mouse leukemia cells in culture was 1.7 .times. 10-5 M, as compared with 1 .times. 10-6 M for FU. The 5-fluorocytosine analog 12 was inactive at up to 1 .times. 10-4 M; the other halogenated derivatives had no effect even at 1 .times. 10-3 M. When 3 was given i.p. in water to P388 leukemic mice at 400 mg/kg or 240 mg/kg, a 75% increase in survival was observed relative to untreated controls; there was no evidence of any host toxicity.