Synthesis of N³-Substituted Uridine and Related Pyrimidine Nucleosides and Their Antinociceptive Effects in Mice

Abstract

Seventy eight N³-substituted derivatives of uridine (1), thymidine (2), 2′-deoxyuridine (3), 6-azauridine (4), 2′,3′-O-isopropylideneuridine (5), and arabinofuranosyluracil (6) were synthesized and their antinociceptive effects were evaluated. N³-(2′,4′-Dimethoxyphenacyl)uridine (1l), N³-(2′,4′-dimethoxyphenacyl)2′-deoxyuridine (3l), and N³-(2′,5′-dimethoxyphenacyl)arabinofuranosyluracil (6m) possessed 93, 86, and 82% of the antinociceptive effects tested by hot plate, respectively. The antinociceptive effects of three derivatives were 5.8, 5.4, and 5.1-folds of the effect of N³-phenacyluridine (1h) (16%), respectively. The structure–activity relationship of N³-substituted pyrimidine nucleosides was also discussed.