Synthesis and biological effects of acyclic pyrimidine nucleoside analogues.
A series of nucleoside analogues has been prepared, wherein the cyclic carbohydrate moiety is replaced by aliphatic side chains attached to cytosine, thymine, uracil, and 5-fluorouracil. The 1-[(2-hydroxyethoxy)methyl] derivatives of these heterocycles were synthesized by reacting the silylated bases with 2-(chloromethoxy)ethyl benzoate, followed by removal of the protecting groups with methanolic ammonia. The hydroxy groups of a number of these derivatives was subsequently replaced by an azido, amino, or carbamoyloxy moiety. The 1-(2-oxo-3-butyl) and 1-(2-oxo-3-nonyl) derivatives of cytosine were also prepared, their synthesis being accomplished by condensation of the silylated heterocycle with the appropriate alpha-halo ketone. At 10(-4) M concentrations, the newly prepared compounds were inactive against leukemia L-1210 cells in culture. However, a number of the agents inhibited the in vitro growth of Escherichia coli K-12, the most potent among these, 1-[(2-hydroxyethoxy)methyl]-5-fluorouracil being active at an IC50 of 1.2 micro M. This compound was equally active in preventing the growth of a 5-fluorouracil resistant strain of E. coli. Some of the analogues were also found to selectively interfere with herpes simplex virus replication in vitro. None of the cytosine derivatives tested served as either substrates or inhibitors of human liver cytosine nucleoside deaminase.
D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D003596:Cytosine / Q000378:metabolism; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009700:Nucleoside Deaminases / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D011741:Pyrimidine Nucleosides; D003596:Cytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase