Syntheses and Biological Activities of N¹-(2-Formylethyl)-5-fluorouracil and Related Compounds

Abstract

Derivatives of 5-fluorouracil (5-FU) substituted at the N-1 position were synthesized in order to investigate their enzymatic conversion to N¹-(2-formylethyl)-5-FU, which is expected to give 5-FU with concomitant release of acrolein. Proton nuclear magnetic resonance spectroscopic studies of authentic N¹-(2-formylethyl)-5-FU suggested that the compound exists in an equilibrium mixture of free aldehyde and cyclic hemiacetal forms. Spontaneous liberation of 5-FU from N¹-(2-formylethyl)-5-FU at neutral pH was demonstrated by thin-layer chromatography using both the authentic compound and N¹-(3-aminopropyl)-5-FU after treatment with amine oxidase, but the release of 5-FU seemed to be limited. Cytotoxicity was observed with N¹-(2-formylethyl)-5-FU and N¹-(3-aminopropyl)-5-FU, but none of the derivatives of 5-FU presently prepared showed a positive effect on P388 leukemia inoculated into mice.