sorivudine and 5-vinyl-1-arabinofuranosyluracil

The structure-activity relationship between (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BV-araU and V-araU) in inhibition of Epstein-Barr virus (EBV) was evaluated. Both V-araU and BV-araU effectively inhibited EBV replication in virus-producer P3HR-1(LS) cells, as determined by DNA-DNA hybridization. The 50% effective doses (ED50) for viral DNA replication were 0.005 and 0.3 microM for V-araU and BV-araU, respectively. The in vitro therapeutic index was 4000 for V-araU and 1300 for BV-araU. Synthesis of EBV-induced polypeptides with molecular weights of 145,000 (145, 140, 130, and 110 kDa) was significantly inhibited by both drugs. Only V-araU inhibited the synthesis of 85-, 55-, and 32-kDa polypeptides by approx. 50%. Kinetic analysis of inhibition and reversibility of EBV DNA replication after removal of the drugs indicated that BV-araU has a more prolonged inhibitory effect than V-araU. These results indicate that the substitution of H by Br in the 5-vinyl group results in marked reduction in anti-EBV activity while prolonging the drug effect and diminishing cytotoxicity.

Topics: Antiviral Agents; Arabinofuranosyluracil; Burkitt Lymphoma; DNA, Viral; Dose-Response Relationship, Drug; Herpesvirus 4, Human; Humans; Peptides; Structure-Activity Relationship; Tumor Cells, Cultured; Viral Proteins; Virus Replication

The 5-substituted 1-beta-D-arabinofuranosyl (araU) analogues, (E)-5-(2-bromovinyl)-araU (BrVaraU) and 5-vinyl-araU (VaraU), which can be considered as structural analogues of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BrVUdR), are potent and selective inhibitors of herpes simplex virus type 1 (HSV-1) replication in vitro. BrVaraU and VaraU have been compared with BrVUdR for their therapeutic effect on acute HSV-1 keratitis in rabbits. Both araU derivatives applied as 0.1% eyedrops suppressed the development of keratitis as monitored by the reduced number of herpes efflorescences. The healing effect of BrVaraU and VaraU was less pronounced than that of 0.1% BrVUdR eyedrops, the difference between BrVUdR and VaraU being statistically significant at the 10th day of treatment. As a further indication of the healing effect the number of cornea with opacities seen after cessation of drug treatment were 3.3, 7.4, 27.6 and 46.9% for the BrVUdR-BrVaraU-, VaraU- and placebo-treated eyes, respectively.

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Drug Evaluation, Preclinical; Keratitis, Dendritic; Ophthalmic Solutions; Rabbits

The effect of (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BrVaraU, VaraU) in comparison to 9-(2-hydroxyethoxymethyl)guanine (ACV) on the proliferation of human lymphoblastoid P3HR-1 cells in culture and on the expression of Epstein-Barr virus capsid antigen (VCA) in the same cells was evaluated. After 7 days of cell growth, at 100 mumol/l the total number of new generations in drug-treated cultures was similar or 5 and 10% below that in drug-free control cultures, for VaraU, ACV, and BrVaraU, respectively. During the same time the percentage of VCA-expressing cells decreased from 6.3% in drug-free cultures to 1.3, 1.5, and 2.0% in cultures treated with VaraU, ACV and BrVaraU, respectively. In VaraU-treated cultures a further decrease in the percentage of VCA-positive cells down to 0.5% was revealed 7 days after drug removal. VaraU was also effective in reducing the proportion of VCA-expressing cells at 10 and 1 mumol/l. At 14 days after drug removal, the inhibitory effect of ACV was nearly reversed, whereas BrVaraU showed a prolonged VCA- suppressing effect.

Topics: Acyclovir; Antigens, Viral; Antiviral Agents; Arabinofuranosyluracil; Capsid Proteins; Cell Line; Herpesvirus 4, Human; Humans; Uridine

Four nucleoside analogues--acyclovir [9-(2-hydroxyethoxymethyl)guanine], bromovinyldeoxyuridine [(E)-5-(2-bromovinyl)-2-deoxyuridine], vinylarauracil 5-vinyl-1-beta-D-arabinofuranosyluracil and bromovinylarauracil [(E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil]--were compared in the therapy of acute keratitis induced in the rabbit cornea by inoculation of the KUPKA strain of herpes simplex virus type 1 (HSV-1). In comparison to placebo-treated animals, the drugs reduced the mean plaque counts in conjunctival swabs as follows: acyclovir to 0.16-1.73%, bromovinyldeoxyuridine to 0.02-0.25%, vinylarauracil to 0.55-5.96% and bromovinylarauracil to 0.12-3.39% of control values. Latency was established to a most limited extent in 1 or 2 out of 5 rabbits treated with vinylarauracil or bromovinylarauracil, respectively. One or 6 out of 84 or 98 explanted ganglion fragments (1.3 or 6%) were positive for HSV-1 as compared to 72 fragments out of 173 (43%) from placebo-treated rabbits. Acyclovir and bromovinyldeoxyuridine completely prevented latency.

Topics: Acute Disease; Acyclovir; Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Chemical Phenomena; Chemistry; Keratitis, Dendritic; Rabbits; Simplexvirus; Uridine

1-beta-D-Arabinofuranosyl-E-5-bromovinyluracil (BVaraU), 1-beta-D-arabinofuranosyl-E-5-iodovinyluracil (IVaraU), 1-beta-D-arabinofuranosyl-E-5-chlorovinyluracil (CVaraU) and 1-beta-D-arabinofuranosyl-5-vinyluracil (VaraU) were examined for antiviral activity against salmon herpesvirus, Oncorhynchus masou virus (OMV) in vitro using Yamame (Oncorhynchus masou) kidney cells (YNK). BVaraU, IVaraU, CVaraU and VaraU were highly active against OMV; 50% inhibitory concentration (IC50): 0.01, 0.003, 0.003, 0.003 microgram/ml, respectively. The IC50 of 5-bromovinyl-2'-deoxyuridine (BVDU) was 0.3 microgram/ml. The lower activity may be due to cleavage of it N-glycosyl linkage by pyrimidine nucleoside phosphorylases (i.e. thymidine phosphorylase) during the incubation period. The arabinofuranosyl counterparts are resistant to this (these) enzyme(s). Both OMV-induced DNA polymerase and cellular DNA polymerase alpha were strongly inhibited by BVaraU 5'-triphosphate (BVaraUTP). In an in vivo study, daily immersion of OMV-infected chum salmon (Oncorhynchus keta) fry into aqueous solution of BVaraU (5 micrograms/ml, 30 min/day, 30 times) did not increase the life span of infected fish.

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cell Line; Chromatography, High Pressure Liquid; DNA Polymerase II; Fish Diseases; Herpesviridae; Herpesviridae Infections; Nucleic Acid Synthesis Inhibitors; Salmon; Uridine

The efficiency of (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BrVaraU, VaraU) as inhibitors of three herpes simplex virus type 1 (HSV-1) strains was assessed in comparison to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BrVUdR), 9-(2-hydroxyethoxymethyl)guanine (ACV), and trisodium phosphonoformate (Na3PFA) using a plaque assay in human embryonic lung fibroblast (HELF) cell cultures. The following order of decreasing activity was found: BrVaraU greater than VaraU greater than BrVU-dR greater than ACV much greater than Na3PFA. In HELF cell cultures, the selectivity indexes of VaraU and BrVaraU were 10 times higher than those of BrVUdR and ACV. Protection of mice from encephalitis and death due to intracerebral (i.c.) infection with a clinical HSV-1 isolate was nearly complete if mice were treated intraperitoneally (i.p.) with two daily doses of VaraU and BrVaraU (100 or 200 mg/kg per day) over a period of 5 or 10 days. The efficacy was similar to ACV, but, using a treatment schedule of three daily i.p. doses over 10 days, with equimolar amounts of the nucleoside analogs, VaraU and BrVaraU (140 and 180 mg/kg per day) were superior to ACV (130 mg/kg per day) (P less than 0.05).

Topics: Acyclovir; Animals; Arabinofuranosyluracil; Bromodeoxyuridine; Cells, Cultured; Encephalitis; Female; Foscarnet; Herpes Simplex; Humans; Mice; Phosphonoacetic Acid; Simplexvirus; Uridine; Viral Plaque Assay