Journal of the Chemical Society. Perkin transactions I p. 457 - 464 (1987)
Update date:2022-08-03
Topics:
Jones, A. Stanley
McClean, Michael J.
Slater, Martin J.
Walker, Richard T.
In order to obtain compounds which give 2'-deoxy-5-vinyluridine (VdUrd) by elimination under basic conditions, a series of 5-(1-substituted ethyl)uracil derivatives has been made.Attemps 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-hydroxymethyl)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 degC 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-trichlorophenylthio)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.
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