Synthesis and biological effects of acyclic pyrimidine nucleoside analogs
- 31 August 1981
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 24 (9), 1078-1083
- https://doi.org/10.1021/jm00141a012
Abstract
A series of nucleoside analogs was 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 group 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 [mouse] leukemias L-1210 cells in culture. 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 .mu.M. This compound was equally active in preventing the growth of a 5-fluorouracil resistant strain of E. coli. Some of the analogs also selectively interfered 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.This publication has 3 references indexed in Scilit:
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