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PubMedDate not supplied

[Biotechnological synthesis of ribavirin. Effect of ribavirin and its various combinations on the reproduction of Vaccinia virus].

The biotechnological method of synthesis of ribavirin, vidarabin, and 6-azauridine by the use of immobilized recombinant enzymatic preparations of nucleoside phosphorylase was improved. The effect of ribavirin and its combinations with the other synthesized nucleosides on the reproduction of Vaccinia virus was studied using cultures of Vero cells. The combination of ribavirin and vidarabin was shown to provide an antiviral effect at lesser concentrations than when these compounds were taken separately. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.

Animals↗
PubMed1995

Cytotoxicity of diterpenes from Premna schimperi and Premna oligotricha.

The cytotoxicity of two diterpenes from Premna schimperi and Premna oligotricha (Verbenaceae) was studied using the MTT assay. Their cytotoxic activity against three human (HeLa, SK.N.SH, and ECV 304) and two murine (L929 and RAW 264.7) carcinoma cell lines varied between 1.5 to 35 micrograms/ml and was comparable with azauridine and chlorambucil.

Animals↗
PubMed2000

Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides.

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.

Animals↗
PubMed1976

Importance of pyrimidine nucleotide salvage pathways for DNA synthesis in skin.

Split-thickness rabbit skins were minced and incubated in vitro with radioactive precursors selected to measure do novo and salvage pathways for pyrimidine nucleotide synthesis. In this system, both the salvage precursors [3H]thymidine and [14C]cytidine were incorporated actively into skin DNA and only [14C]cytidine into skin RNA. In contrast, the de novo precursor [14C]orotic acid labeled skin RNA extensively but did not significantly label skin DNA. An unusually high ratio of specific activities of UMP:CMP in RNA was observed when [14C]orotic acid was used as a nucleotide precursor. Methotrexate effectively blocked thymidylate synthesis do novo but did not inhibit DNA synthesis as determined by [3H]thymidine incorporation into DNA thymidylate residues or by [14C]deoxycytidine incorporation into DNA deoxycytidylate residues. Azauridine inhibited labeling of RNA by [14C]orotic acid to a greater extent than labeling of DNA by [3H]thymidine. These results suggest that in rabbit skin, cytidine nucleotides are utilized more effectively than uridine nucleotides for deoxypyrimidine biosynthesis, that DNA synthesis is primarily dependent upon salvage mechanisms to supply deoxypyrimidine nucleotides, and that inhibition of thymidylate synthesis by methotrexate does not inhibit DNA synthesis in this system.

Animals↗
PubMed2006

Inhibition of human coronavirus NL63 infection at early stages of the replication cycle.

Human coronavirus NL63 (HCoV-NL63), a recently discovered member of the Coronaviridae family, has spread worldwide and is associated with acute respiratory illness in young children and elderly and immunocompromised persons. Further analysis of HCoV-NL63 pathogenicity seems warranted, in particular because the virus uses the same cellular receptor as severe acute respiratory syndrome-associated coronavirus. As there is currently no HCoV-NL63-specific and effective vaccine or drug therapy available, we evaluated several existing antiviral drugs and new synthetic compounds as inhibitors of HCoV-NL63, targeting multiple stages of the replication cycle. Of the 28 compounds that we tested, 6 potently inhibited HCoV-NL63 at early steps of the replication cycle. Intravenous immunoglobulins, heptad repeat 2 peptide, small interfering RNA1 (siRNA1), siRNA2, beta-D-N(4)-hydroxycytidine, and 6-azauridine showed 50% inhibitory concentrations of 125 microg/ml, 2 microM, 5 nM, 3 nM, 400 nM, and 32 nM, respectively, and low 50% cytotoxicity concentrations (>10 mg/ml, >40 microM, >200 nM, >200 nM, >100 microM, and 80 microM, respectively). These agents may be investigated further for the treatment of coronavirus infections.

Animals↗
PubMed1974

Herpes simplex virus skin infection in hairless mice: treatment with antiviral compounds.

A hairless mouse-herpes simplex virus skin infection experimental model was used to evaluate the efficacy of the antiviral compounds 9-beta-d-arabinofuranosyladenine (ara-A), 5-iodo-2'-deoxyuridine (IUdR), and 6-azauridine (aza-U). Ara-A and IUdR, when administered intraperitoneally by several different dosage schedules, reduced the severity of cutaneous herpetic lesions and the incidence of paralysis and increased significantly the number of survivors. A more rapid healing of the lesions and an increase in the mean survival time also was observed. A delay of 24 to 48 h in the initiation of treatment after the infection was more effective than treatments started at the time of inoculation. Treatment with ara-A was somewhat superior to that with IUdR, but aza-U was totally ineffective. Enhancement of the evolution of the infection was noted after treatment with aza-U.

Adenine↗
PubMed1976

Induction of measles virus hemagglutinin in a persistently infected, nonvirogenic line of cells (BGM/MV).

BGM/MV cells carry measles virus antigens and nucleocapsid-like structures in their cytoplasm. There is no infectious virus demonstrable, and measles virus-induced cell surface changes detectable by hemadsorption (HAD) are absent. Treatment of cells with actinomycin D or cycloheximide or enucleation of cells with cytochalasin B induced surface changes in that the cells became HAD positive. 6-Azauridine treatment of cells did not inhibit the induction of HAD, suggesting that RNA synthesis was not required. Cycloheximide treatment of cells induced by enucleation inhibited the development of HAD, suggesting a requirement for protein synthesis.

Animals↗
PubMed1982

Fetal fuels. V. Ketone bodies inhibit pyrimidine biosynthesis in fetal rat brain.

Ketonemic states complicating late pregnancy are accompanied by lower brain weights in the newborn. Potential mechanisms whereby ketone bodies might inhibit cell proliferation were therefore examined in the fetal rat brain slice by measuring their impact on the de novo pathway for pyrimidine biosynthesis. DL-beta-hydroxybutyrate (10.8 mM) and acetoacetate (5.4 mM) were both found to diminish the incorporation of NaH14CO3 into [14C]UMP by 30%. This effect was similar in fetal tissues from fed and 48-h starved mothers. Graded concentrations of DL-beta-hydroxybutyrate (1.4-43.2 mM) resulted in a progressive inhibition that could not be explained either by isotope dilution consequent to ketone body oxidation or by a generalized inhibition of protein synthesis. The inhibition was not reversed with 10 mM glutamine, the principal nitrogen substrate for de novo biosynthesis of pyrimidines. When the conversion of orotic acid into UMP was blocked with 6-azauridine, DL-beta-hydroxybutyrate (10.8 mM) inhibited the incorporation of NaH14CO3 into orotic acid by 28%. By contrast, maximally inhibitory concentrations of this ketone body (43.2 mM) had no effect on the incorporation of [6-14C]orotic acid into [14C]UMP. Is is concluded that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal brain slices and that they do so at a site proximal to orotic acid formation.

Animals↗
PubMed1993

Gene amplification and chromosome rearrangements: a study of a single cell lineage selected for amplification and deamplification of the UMP synthase gene.

The UMP synthase gene is stably amplified in Chinese hamster lung cells selected for resistance to pyrazofurin (PF) and 6-azauridine (6AUR), inhibitors of the decarboxylase activity of the bifunctional UMP synthase enzyme. The amplified DNA is located intrachromosomally as expanded chromosomal regions (ECRs). Growth of these cells in 5-fluorouracil enables rapid selection of cells that have undergone deamplification and consequently lost resistance to PF + 6AUR. Detailed cytogenetic analyses and fluorescence in situ hybridization on three consecutive amplification-deamplification cycles in descendants of the same cloned cell showed a unique position and structure for the ECR. In the first cycle of amplification, the ECR forms a homogeneously staining region on a small marker chromosome (M3). In the second cycle of amplification, a chromosomal break was noted at the site of the endogenous UMP synthase gene on another derivative chromosome, M2, with amplification resulting in an abnormally banded region on a third marker (M3). The third cycle of amplification produced a cell line with an ECR on the distal portion of M2. This ECR was unstable, showing variations in size as well as translocations and other chromosome rearrangements. Our data, taken in its entirety, suggest a relationship between amplification as an ECR and chromosome rearrangements in Chinese hamster cells.

Amides↗
PubMed1975

The treatment of psoriasis with azaribine.

An open study was made of 25 patients with severe, recalcitrant psoriasis treated with azaribine (6-azauridine triacetate). Most patients received 125 mg/kg/day for a period of 8 weeks. A good to excellent response with 60-100% clearing of lesions was observed in 14 patients and a fair response with 40-60% improvement in another 6 patients. Thus 20 patients (80% of the series) exhibited a favorable clinical response. 16 of these 20 patients relapsed to approximately pretreatment status within 1 month after stopping therapy. The most frequently observed side-effects were mild reversible anemia, fatigue and mild transient gastrointestinal symptons. 8 patients (32% of the series) exhibited sufficient toxicity to necessitate the discontinuance of therapy. 1 patient experienced an unexplained femoral arterial thrombotic episode while on the drug. Azaribine may find a place in the therapy of severe psoriasis particularly in patients with hepatic disease. However, further studies of its potential for toxicity are indicated.

Adolescent↗
PubMed1996

Characteristics of the anticoccidial activity of 6-azauracil.

The characteristics of anticoccidial activities of 6-azauracil (AzU) were investigated in the battery trials utilizing the White Leghorn cockerels, which were infected with Eimeria tenella, E. necatrix, E. acervulina, E. maxima and/or E. brunetti. AzU was mixed into the basal starter feed and fed ad libitum to the birds from 1 day before the inoculation of oocysts to the time of necropsy. AzU showed remarkable anticoccidial activity against E. tenella and E. necatrix infections at doses of 1,000 ppm in feed or more, and fairly good effect against E. acervulina infection at the dose of 4,000 ppm in feed. Inadequate effect against E. maxima infection and null in effect against E. brunetti at the dose of 4,000 ppm were resulted for this drug. The effect of 6-azauridine, ribonucleoside of AzU against E. tenella and E. necatrix infections at 1,000 ppm was tested and revealed negative results. In the test with AzU-resistant line of E. tenella, cross resistance was confirmed between AzU and emimycin riboside, a uridine analogue. Activity of AzU was studied in vitro against E. tenella in chick kidney cells. AzU inhibited the development of the first- and second-generation schizonts at 100-200 ppm in the medium. Degenerated parasites were observed.

Animals↗
PubMed1975

Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine.

The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.

Azaguanine↗
PubMed1979

[Mutagenic alterations of antibody biosynthesis].

The investigations of changes of antibody affinities were carried out with 182 immuned CBA mice under the influence of the mutagens. The mice were injected with ethylene imine and its derivatives, 6-azauridine, cyanurchloride, theobromine, glyoxal, at a dose of 100 mg/kg 2 days before, simultaneously and in 2 and 5 days after the immunization. The indices of the functional affinity of antibodies (the mean constant of true association, the standard free energy, the concentration of the hapten binding sites, the heterogeneity index, the level of IgG and its Fab- and Fc-fragments) were determined within 5, 10 and 20 days. Three groups of changes of antibody affinities in immuned mice were observed under the influence of mutagens: a) disassotiative changes with acute fall of affinities; b) erase changes; c) variable changes with discrete and corrective displacement of some affinities indices. Analysis of the data obtained suggests the existence of two forms of the mutagen immunodepression: 1) real immunodepression with a parallel fall of primary and secondary indices of antigen-intibody interaction; and 2) functional immunodepression with a fall of secondary indices. Polyfunctionality of the inhibition effect of alkyl mutagens is demonstrated.

Animals↗
PubMed1981

Effect of inhibitors of the de novo pyrimidine biosynthetic pathway on serum uridine levels in mice.

Since C57BL X DBA F1 (hereafter called BDF1) mice possess a relatively constant concentration of serum uridine [9.7 +/- 1.3 (S.D.) nmol/ml], circulating uridine is available to cells with an intact pyrimidine salvage pathway and thus could influence the effectiveness of certain antitumor agents which inhibit de novo pyrimidine biosynthesis and whose cytotoxic properties are reversed by uridine. Three inhibitors of the de novo pyrimidine biosynthetic pathway were studied to determine their effects on circulating uridine concentration in BDF1 mice. Pyrazofurin and 6-azauridine were found to have no significant effect on serum uridine levels when administered as a single dose or on 4 consecutive days. In contrast, N-(phosphonacetyl)-L-aspartate reduced serum uridine levels by 55% when administered either as a single dose or on 4 consecutive days. This reduction could contribute to the antitumor effectiveness of N-(phosphonacetyl)-L-aspartate by limiting the rescue of cells possessing a salvage pathway. D-Galactosamine, a stimulator of the de novo pyrimidine pathway, was also studied and found to increase total liver uridine (uridine plus uracil nucleotides and uridine diphosphate esters) by 4-fold at 8 hr, returning to normal by 24 to 48 hr. However, these large effects were not reflected in the serum.

Amides↗
PubMed1984

The role of cell type in transport and metabolic conversion of antiviral substances.

The transport and metabolic conversion of 6-azauridine differed when compared in HeLa and chick embryo (CE) cells. The values of 9-(S)-(2, 3-dihydroxypropyl) adenine transported into the cells were found different for ZP cells (rabbit lung cell line), HeLa and CE cells. These differences were less expressed if relating the values of cellular uptake and metabolic conversion to the cell volume of the respective cell type. The differences seem to play a role in quantitation of the antiviral potency of the compounds in different host cells.

Animals↗
PubMed1977

Inhibition of the lethality of bleomycin A5 in L-cells by hirudonine.

The lethality of several individual bleomycin derivatives, i.e., the spermidine derivative (A5), The dimethyl sulfonium aminopropyl derivative (A2), and the agmatine derivative (B2), was compared on mouse fibroblasts. The spermidine derivative, bleomycin A5, was the most toxic, producing more than a 2-log drop in clonability in 50 hr at 20 microng/ml. 6-Azauridine, a relatively nonlethal inhibitor of RNA synthesis and cell multiplication, produced a 60% decrease of adenine incorporation into nucleic acids without inhibiting the lethal action of A5. This result differed from the effects of inhibition of RNA synthesis on the lethality of A5 in Escherichia coli. Hirudonine (1,8-diamidino-spermidine) markedly and specifically inhibited the lethal effects of A5 in L-cells but not in E. coli. However, hirudonine did not affect the toxicity of A2 and B2, separately or together, as it did in the mixture used clinically. Nor did arcaine (diamindinoputrescine) reduce the lethality of the agmatine (monoamidinoputrescine) derivative, B2.

Amidines↗
PubMed1979

Abnormal regulation of de novo purine synthesis and purine salvage in a cultured mouse T-cell lymphoma mutant partially deficient in adenylosuccinate synthetase.

The isolation and characterization of a mutant murine T-cell lymphoma (S49) with altered purine metabolism is described. This mutant, AU-100, was isolated from a mutagenized population of S49 cells by virtue of its resistance to 0.1 mM 6-azauridine in semisolid agarose. The AU-100 cells are resistant to adenosine mediated cytotoxicity but are extraordinarily sensitive to killing by guanosine. High performance liquid chromatography of AU-100 cell extracts has demonstrated that intracellular levels of GTP, IMP, and GMP are all elevated about 3-fold over those levels found in wild type cells. The AU-100 cells also contain an elevated intracellular level of pyrophosphoribosylphosphate (PPriboseP), which as in wild type cells is diminished by incubation of AU-100 cells with adenosine. However AU-100 cells synthesize purines de novo at a rate less than 35% of that found in wild type cells. In other growth rate experiments, the AU-100 cell line was shown to be resistant to 6-thioguanine and 6-mercaptopurine. Levels of hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) measured in AU-100 cell extracts, however, are 50-66% greater than those levels of HGPRTase found in wild type cell extracts. Nevertheless this mutant S49 cell line cannot efficiently incorporate labeled hypoxanthine into nucleotides since the salvage enzyme HGPRTase is inhibited in vivo. The AU-100 cell line was found to be 80% deficient in adenylosuccinate synthetase, but these cells are not auxotrophic for adenosine or other purines. The significant alterations in the control of purine de novo and salvage metabolism caused by the defect in adenylosuccinate synthetase are mediated by the resulting increased levels of guanosine nucleotides.

Adenylosuccinate Synthase↗
PubMed1993

Purine control of mouse oocyte maturation: evidence that nonmetabolized hypoxanthine maintains meiotic arrest.

Hypoxanthine is present in preparations of follicular fluid and has been shown to suppress the spontaneous meiotic maturation of mammalian oocytes in vitro. The present experiments examined the possible role of hypoxanthine metabolism in mediating this meiotic arrest. Four putative inhibitors of the enzyme, hypoxanthine phosphoribosyltransferase (HPRT), which metabolizes hypoxanthine to inosine monophosphate, were tested on lysates of oocyte-cumulus cell complexes. At a concentration of 1 mM, 6-mercapto-9-(tetrahydro-2-furyl)-purine (MPTF) and 6-mercaptopurine (6-MP) suppressed enzymatic activity by 86% and 98%, respectively, while 6-azauridine and 2,6-bis-(hydroxyamino)-9-beta-D-ribofuranosyl-purine had no effect. MPTF and 6-MP increased the inhibitory effect of hypoxanthine on germinal vesicle breakdown, but the other agents did not. The 2 active agents had similar effects on salvage activity and hypoxanthine-maintained meiotic arrest in denuded oocytes. Also, oocytes from XO mice were more sensitive to the meiosis-arresting action of hypoxanthine than oocytes from XX littermates, which have twice the HPRT activity. The actions of the HPRT inhibitors were not due to their conversion to nucleotides via HPRT and negative feedback on purine de novo synthesis, because azaserine and 6-methylmercaptopurine riboside, which are more potent inhibitors of de novo synthesis, had a stimulatory, rather than inhibitory, effect on hypoxanthine-arrested oocytes. Furthermore, several lines of evidence indicate that metabolism of hypoxanthine to xanthine and uric acid by xanthine oxidase does not mediate the inhibitory action of this purine base on meiotic maturation. The data therefore suggest that nonmetabolized hypoxanthine is responsible for the meiotic arrest observed, most likely through suppression of cAMP degradation.

Animals↗