Synthesis and biological effects of acyclic pyrimidine nucleoside analogs

Abstract

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.

An approach to the ecological significance of chemically mediated bio-activity in Mediterranean benthic communities

“…(HSV) cultured in kidney cells of monkey (CV-1) and with vesicular stomatitis virus (VSV) in kidney cells of hamster (BAK) a s previously described (Schroeder et al 1981). All activities (antimicrobial, antifungal, antimitotic and antiviral) were graded on 4 levels, from 0 (non-active) to 3 (very active).…”

Uracil analogues of the acyclonucleoside 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]- methyl]guanine (BIOLF-62)

“…While many such analogues have an intact but modified furanose ring, others can be considered as ring-open nucleoside analogues (2)(3)(4). We have introduced a novel ring-open nucleoside structure 1 (5 -7) which possesses all of the chemical functionality of deoxyribonucleosides but which lacks the rigid furanose ring structure.…”

Acyclic Pyrimidine Nucleoside Analogues: Influence on Growth of L5178y Mouse Lymphoma Cells and Antiherpes Activity in KB Cells

“…Two new acyclic guanine derivatives have been de veloped which show marked antiherpesvi rus activity [1,12,21,22], As mentioned previously, no acyclic pyrimidines have shown great promise in this regard [2,9,10,18].…”

“…Acyclic pyrimidine nucleosides have al so been synthesized and evaluated for an tiviral activity [2,3,9,10,18]. Little or no antiherpesvirus activity has been found for several l-(2'-hydroxyethoxymethyl) derivatives of cytosine, or uracil [2,8,9,18] or for l-(2'-aminoethoxymethyl)-uracils [10], We have explored the activity of a number of uracil and cytosine derivatives with one of the following acyclic side chains: 2-hydroxyethoxymethyl, 2-aminoethoxymethyl, or 1,3-dihydroxypropoxymethyl.…”

“…Little or no antiherpesvirus activity has been found for several l-(2'-hydroxyethoxymethyl) derivatives of cytosine, or uracil [2,8,9,18] or for l-(2'-aminoethoxymethyl)-uracils [10], We have explored the activity of a number of uracil and cytosine derivatives with one of the following acyclic side chains: 2-hydroxyethoxymethyl, 2-aminoethoxymethyl, or 1,3-dihydroxypropoxymethyl. We primarily concentrated on 5-substitutions as have other investigators [2,9,24], Therefore, a number of ana logues of pyrimidine acyclic nucleosides have been synthesized and analyzed for cell growth inhibitor potency and for anti herpes activity.…”