Synthesis of 5-(1-substituted ethyl)uracil derivatives and some of their chemical and biological properties

Abstract

In order to obtain compounds which would give 2′-deoxy-5-vinyluridine (VdUrd) by elimination under basic conditions, a series of 5-(1-substituted ethyl)uracil derivatives has been made. Attempts to obtain 5-(1-alkyl- or -aryl-sulphonyloxy) derivatives were unsuccessful because elimination to give the 5-vinyl derivatives was extremely easy. 5-(1-Acyloxyethyl) derivatives did not eliminate, but with aqueous alkali gave 5-(1-hydroxyethyl)uracil derivatives. Reaction of VdUrd with a series of arenethiols gave 5-(1-arylthioethyl)-2′-deoxyuridines. In the absence of radical inhibitors 5-(2-arylthioethyl)-2′deoxyuridines were the major products. The arylthio compounds were oxidized to the corresponding sulphoxides and sulphones. Treatment of these 5-(1-substituted) derivatives with potassium t-butoxide in dimethylformamide gave VdUrd. As expected the reaction rate was greatest with the compound which had the best leaving group. However, with aqueous alkali the compounds gave 2′-deoxy-5-(1-hydroxyethyl)uridine and at pH 7.6 at 37 °C they were stable. When N-3 of the uracil ring was alkylated the elimination was faster. The implication of this result for the mechanism of the elimination is discussed. Two of the compounds synthesized, namely 2′-deoxy-5-[1-(2,4,5-trichlorophenylthio)ethyl]uridine and 2′-deoxy-3-methyl-5-[1-(2,4,5-trich lorophenylthio)ethyl]uridine, showed activity against vaccinia virus and murine L1210 leukaemia cells at a concentration. of 30–40 µg/ml, and 2′-deoxy-5-[(2-phenylthio)ethyl]uridine, had activity against different strains of herpes simplex viruses types 1 and 2 at a concentration of 20 µg/ml.