Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
Design, synthesis, biological evaluation, and molecular modeling of novel nucleoside analogs as potential anti-tumor and anti-viral agents.
Diss Abstr Int [B]; 55(6):2219 1994. Unique Identifier : AIDSLINE ICDB/95615355 Chen X; Univ. of North Carolina at Chapel Hill
Abstract:
The goal of this research is to develop two series of novel nucleoside analogs as potential antitumor and antiviral agents. All synthesized compounds were screened for cytotoxicity using the SV-28 tumor cell line and their antiviral activity was tested against HIV-1 and herpes simplex virus-1 by plaque reduction assays. The first series of compounds are thymidine analogs containing a hydroxyalkylammonium (or amino) group either at the 5' position or at a corresponding position in the acyclic thymidine analogs. In order to increase the lipophilicity of these compounds and potentially enable them to cross the cell membrane, the free hydroxy group was esterified with a long hydrocarbon chain. The hexadecanoyl analogs (compounds 1-c, 1-d, 7-c, and 7-d) showed moderate antitumor cytotoxicity against SV-28 and KB cell lines (IC50 approx 20 uM). While compounds 5, 6, and 7-a showed marginal anti-HIV activity (IC50 approx 50 to 130 uM), none of the compounds showed antiherpes activity. The second series of compounds are nucleoside analogs containing a boronic acid moiety. Both purine and pyrimidine analogs containing a butyl boronic acid have been synthesized; several showed moderate antitumor cytotoxicity. Compound 9 (dihydroxylborylbutyl-6-chloropurine) showed moderate activity against HIV-1 with an IC50 value of 9 uM. Compound 11 (dihydroxylborylbutyl guanine), which may be seen as an analog of acyclovir, showed weak antiherpes activity (IC50 approx 100 uM). In order to study the conformation of the boronic acid containing compounds by molecular mechanics, parameters for the boronic acid moiety were needed which were not available. Since the boronic acid functionality has been incorporated into many biologically important compounds with interesting pharmacological results, accordingly, ab initio calculations were performed to obtain both the bonded and nonbonded parameters for boronic acid. The nonbonded parameters were tested by performing a free energy perturbation simulation to calculate the solvation free energy, and the calculated values compared favorably with the experimental values. The calculated parameters were used in a conformational study of the compounds in the boronic acid containing nucleoside analogs. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-29396)
Keywords: Antineoplastic Agents/METABOLISM/*THERAPEUTIC USE Antiviral Agents/METABOLISM/*THERAPEUTIC USE Boronic Acids/METABOLISM HIV-1/*DRUG EFFECTS Purine Nucleosides/METABOLISM/THERAPEUTIC USE Simplexvirus/DRUG EFFECTS THESIS 951230
M95C3241
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Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.
