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PubMed1964

THE DEMONSTRATION OF THE SITE OF ACTION OF THE ANTIMETABOLITE DRUG 6-AZAURIDINE BY THE USE OF LEUCOCYTE CULTURES.

The ability of the lymphocyte cultured in vitro to transform and synthesize deoxyribonucleic has been utilized to locate the site of action of a new antimetabolite 6-azauridine which acts by inhibiting nucleic acid synthesis. The exact site can be demonstrated by incorporating into the cultures nucleotides occurring distal and proximal to the presumed site of action of 6-azauridine.

Antimetabolites↗
PubMed1992

The 6-azauridine analogues possessing sedative and hypnotic effects.

Pharmacological effects of 6-azauridine (4) analogues were evaluated using hypnotic activity, pentobarbital (PB)-induced sleep prolongation and locomotor activity as indices. Compound 4, N3-benzyl- (10), N3-o-xylyl- (11), N3-m-xylyl- (12), N3-p-xylyl- (13), N3-alpha-phenylethyl-substituted 6-azauridine (14) exhibited hypnotic activity and PB-induced sleep prolongation, whereas N3-alkyl substituted analogues (methyl-, ethyl-, n-propyl-, n-butyl- and allyl-substitution) did not. Compound 4 and xylyl analogues (11-13) significantly decreased locomotor activity of mice by i.c.v. injection and produced motor incoordination. The results indicate that 4 and its benzyl related analogues, but not alkyl analogues have depressant effects on the central nervous system (CNS).

Animals↗
PubMed1989

Identification of 6-azauridine triphosphate in L1210 cells and its possible relevance to cytotoxicity.

L1210 cells treated with 1 mM 6-azauridine (AzUrd) (concentration causing 50% inhibition of cell growth, 3 microM) continued to divide at a reduced rate for 72 h before stopping. However, a 24-h treatment was lethal to 99% of the cells, as determined by colony formation. To investigate the mechanism for this delayed cytotoxicity, the metabolism of AzUrd was studied. Cells incubated with AzUrd contained a new 254 nm-absorbing component, not found in control cells. It appeared to be 6-azauridine-5'-triphosphate, since it was the only peak in the triphosphate region of the chromatogram which contained 3H after incubation of cells with [3H]AzUrd. Incorporation of [3H]AzUrd into the acid-insoluble fraction (nucleic acids) was also detected. A role for this incorporation in the mechanism of AzUrd cytotoxicity was strongly suggested by the observation that cordycepin (0.01 mM) partially protected cells from the lethality of AzUrd, presumably by preventing its incorporation into RNA. The previously known inhibition of pyrimidine de novo synthesis by AzUrd was confirmed by a decrease in the intracellular contents of UTP and CTP in AzUrd-treated cells. Therefore, we propose that the inhibition of pyrimidine de novo synthesis and the incorporation into nucleic acid(s) may act in concert to produce the cytotoxic effects of AzUrd.

Animals↗
PubMed1979

Effect of 6-azauridine on de novo pyrimidine biosynthesis in cultured Ehrlich ascites cells. Orotate inhibition of dihydroorotase and dihydroorotate dehydrogenase.

The inhibition of dihydro-orotase (E 3.5.2.3) and dihydroorotate (DHO) dehydrogenase (dihydro-orotate oxidase, EC 1.3.3.1) by cellular orotate (OA) in Ehrlich ascites cells was studied by measuring the accumulation of the intermediates of de novo pyrimidine biosynthesis at various times after the addition of 6-azauridine to the culture medium. The addition of 6-azauridine resulted in the accumulation of orotidine, OA, DHO, and carbamyl aspartate (CAA). The use of the observed ratios of [CCA]/[OA] and [DHO]/[OA] and other known constants allowed us to calculate that the increased cellular OA concentration caused primarily an inhibition of DHO dehydrogenase rather than an inhibition of dihydroorotase. A constant ratio of [CAA]/[DHO] was observed which probably indicates that the interconversion of these two intermediates catalyzed by dihydroorotase is near equilibrium in these cells as has been observed in vitro (Christopherson, R.I., Matsuura, T., and Jones, M.E. (1978) Anal. Biochem. 89, 225-234). It is suggested that the probable intracellular accumulation of CAA in patients with oroticaciduria may have significant secondary effects.

Amidohydrolases↗
PubMed1984

Quantitative determination of nucleosides and their phosphate esters--1. The acidic nucleosides, 3-deazauridine and 6-azauridine.

A relatively rapid, high-resolution chromatographic procedure, using mini-columns of DEAE cellulose equilibrated with 10 mM sodium phosphate, pH 6.0, is described in sufficient detail to permit ready replication. This initial paper demonstrates the quantitative separation, using suction, of the acidic nucleosides, 3-deazauridine and 6-azauridine, from their phosphorylated derivatives. The chemically stable, tritium-labeled nucleosides are eluted from the mini-columns (capacity approximately equal to 1.8 ml) with 10 mM sodium phosphate, pH 6.0; subsequently, the nucleotides are eluted completely with 0.5 M HCl/0.5 M NaCl. Quantitation is based on liquid scintillation counting of aliquots of the eluates.

3-Deazauridine↗
PubMed1989

Resistance to pyrazofurin and 6-azauridine in normal MC3T3-E1 murine osteoblasts.

Stable variants resistant to pyrazofurin (PF) and 6-azauridine (AZUrd) were serially selected in increasing drug concentrations from an MC3T3-E1 nontumorigenic murine osteoblastic cell line. Monophosphates of both AZUrd and PF competitively inhibit orotidine-5'-monophosphate decarboxylase (ODCase) activity of the UMP synthase multifunctional enzyme. When compared to the wild type cells, the AZUrdr and PFr lines were 3000- and 10,000-fold more resistant, respectively. Flow cytometry indicated tetraploidy in wild type cells and a reduction of DNA content in both resistant cell lines. DNA dot blot analysis showed no amplification of the gene coding for UMP synthase in either AZUrdr or PFr cells. Measurements of UMP synthase showed a 6-fold higher activity in AZUrdr cells and no significant difference in PFr cells as compared to wild type. Sensitivity to 5-fluorouracil was increased in the AZUrdr line as opposed to PFr and normal cell lines, indicating an increased orotate phosphoribosyltransferase activity in the AZUrdr cells. In comparison to wild type cells, PFr cells were 100-fold resistant to 6-methylmercaptopurine riboside, suggesting a lack of adenosine kinase activity. The control and AZUrdr cells showed equal sensitivity to 5-fluorouridine, thus indicating unchanged uridine kinase levels. While PFr cells were not cross-resistant to AZUrd, the AZUrdr cells were cross-resistant to PF. These results indicate the possibility of an altered ODCase active site. Although amplification of unrelated sequences cannot be excluded, our findings show that bone tetraploid, nontumorigenic cells acquire drug resistance through mechanisms other than the amplification of a target gene and that this resistance is accompanied by the partial loss of a chromosomal complement.

Amides↗
PubMed2001

In vitro metabolism studies of the prodrug, 2',3',5'-triacetyl-6-azauridine, utilizing an automated analytical system.

The purpose was to study in vitro metabolism of 2',3',5'-triacetyl-6-azauridine (1) by porcine liver esterase (PLE) and in human plasma using an automated analytical system developed previously. A gradient-LC method was developed to study the concentration-time course of 1 and its metabolites. A fast-LC assay was used to study the temperature effect on the metabolism of 1 by the PLE. 1 and all of its proposed possible metabolites were separated by the gradient-LC method in less than 10 min. Two simplified kinetic schemes were developed to describe the time course of 1, the intermediates and final metabolites with only five rate constants for the metabolisms of 1 by PLE and four rate constants in human plasma. Both enthalpy and entropy of activation in the in vitro metabolism of 1 by PLE were obtained.

Algorithms↗
PubMedDate not supplied

Site specific incorporation of 6-azauridine into the genomic HDV ribozyme active site.

The HDV ribozyme is proposed to catalyze its self cleavage reaction by a proton transfer mechanism wherein the N3 of its C75 acts as a general acid. The C75 to U mutation, which raises the N3 pKa from about 4 to almost 10. abolishes all enzymatic activity. To test if a U analogue with a neutral pKa can restore ribozyme function we incorporated 6-azauridine (n6U), a uridine analogue with histidine-like N3 pKa. into the genomic HDV ribozyme active site by 2'-O-ACE oligoribonucleotide protection chemistry. The resulting ribozymes were analyzed for their ability to undergo the HDV ribozyme cis-cleavage reaction. Incorporation of n6U at nucleotide position 75 did not restore ribozyme function compared to the U75 mutant. This suggests that the HDV ribozyme reaction mechanism involves more than positioning of a neutral nucleobase at the active site and implies that the exocyclic amino group of C75 participates in establishing the proper active site fold.

Azauridine↗
PubMed1976

Acetylation and cleavage of purine nucleosides. Synthesis of 6-azauridine, 5-fluorouridine, and 5-methyluridine.

Inosine (I) when acetylated with acetic anhydride in the presence of acetyl chloride in acetic acid solution (the so called "acid acetylation"), affords an acetylated nucleoside III (75%) along with cleavage products of the nucleoside (hypoxanthine, 19%). The reaction of I with acetyl chloride (7 days) results in the formation of hypoxanthine (95%) and triacetylribofuranosyl chloride (IV) isolated in the form of tetraacetylribofuranose (47%). The acetylated purine nucleoside affords a similar result by reaction with acetyl chloride or acetyl bromide. 2'-Deoxyuridine gives a diacetyl derivative (80%) by reaction with acetyl bromide. On treatment with acetyl bromide, the nucleoside bond of purine nucleosides is quantitatively cleavaged (4 h, 20 degrees C) with the formation of tri-O-acetyl-D-ribofuranosyl bromide (X). The halogenose X affords pure beta-anomers, namely, 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose (75%), the triacetyl derivatives of 5-methyluridine (XVIIa; 75%, referred to guanosine), 6-azauridine (XVIII; 71%), and 5-fluorouridine (XIXa; 75%).

Azauridine↗
PubMed1977

Antiviral action and selectivity of 6-azauridine.

6-Azauridine (AzUrd) is a broad-spectrum antimetabolite that inhibits both DNA and RNA virus multiplication. Prior work indicated that several AzUrd-sensitive viruses induced an increase in the level of uridine kinase, and this might explain the selective activity of AzUrd on such viruses. Present studies compared AzUrd sensitive and resistant viruses with respect to their orotic acid pathways by labeling cells with [14C]-orotic acid during the latent period of viral infection. No differences were detected by this method with either vaccinia, Newcastle disease, or vesicular stomatitis viruses. AzUrd inhibits transport of orotic acid into the cell by 30%, while incorporation of orotic acid into cellular RNA is inhibited by 50% (taking into consideration the 30% already noted) when the highest concentration of antimetabolite is used. This suggests that, in addition to blocking orotidylic acid decarboxylase, AzUrd may act on some other site (sites) of action in the inhibition of virus multiplication.

Antiviral Agents↗
PubMed1975

Paramyxovirus-avian cell relationship: discrepant impact of 6-azauridine on virus production by susceptible and less susceptible cells.

The replication of mumps virus in susceptible chicken embryonic heart cells was escalated by daily treatment of cultures with 6-azauridine (6-AU). On the other hand, virus production by less susceptible liver cells was depressed by 6-AU. The population of infected susceptible cells was not increased, but the release of virus by infected susceptible cells was enhanced 20-fold by 10 mug of 6-AU per ml. Less susceptible cells, which incorporated less ribonucleic acid and protein precursor than susceptible cells, sustained a constant level of viral release during 6-AU treatment; however, the number of infected less susceptible cells underwent substantial decline.

Animals↗
PubMed1973

Measles virus ribonucleic acid and protein synthesis: effects of 6-azauridine and cycloheximide on viral replication.

Cycloheximide and 6-azauridine were employed to study the time course of measles virus protein and nucleic acid syntheses in AV3 cells. Synthesis of ribonucleic acid (RNA) essential for infectivity was first detected at 6 hr and increased concurrently with the formation of essential protein. Maximum levels of virus-specific RNA and protein were present by 18 hr, a time when only 5% of progeny virus was detected. Essential RNA and protein syntheses preceded the formation of infectious virus by at least 10 to 12 hr. The time course of RNA and protein syntheses essential for the formation of complement-fixing (CF) antigen and salt-dependent agglutinin (SDA) was also determined. RNA synthesis essential for the formation of SDA was first detected at 2 hr and was present maximally by 6 hr, whereas SDA-protein increased concurrently with the protein essential for infectivity. This suggested that the last protein essential for infectivity may be SDA. RNA synthesis essential for the formation of CF antigen was first detected at 4 hr, while CF-protein increased at 5 hr and preceded SDA-protein and protein essential for infectivity by approximately 3 hr. Reversal of inhibition of protein synthesis by cycloheximide indicated that early protein synthesis (1 to 3 hr) was required for the formation of infectious virus. The data suggest that the relatively long eclipse period observed with measles virus is related to a long maturation period rather than to late formation of early proteins, viral RNA, or structural proteins.

Amnion↗
PubMed1982

Effect of 6-azauridine and pyrazofurin on fibrinolysis by L1210 leukemic cells.

The expression of plasminogen activator activity (PA) by L1210 leukemic ascitic cells, obtained from the peritoneum of BDF1 mice, increases in the terminal stages of the disease. Treatment of mice carrying advance leukemia (day 6 following inoculation with 10(6) cells i.p.) with 6-azauridine (AzUR) results in prolonged survival (2-3 days) and also in increased expression of PA activity by the ascitic cell population. Similar treatment with pyrazofurin (PF), another inhibitor of orotidylate decarboxylase and of de novo pyrimidine synthesis, fails to produce either of these effects. Neither AzUR or PF, given at the early stage of tumor growth (day 3), extend the life span nor do they cause increase of the PA activity. Thus, the elevation in PA activity following treatment with AzUR is associated with the asymptotic stage of the disease and this phenomenon correlates positively with the life-prolonging effects of this drug. An analysis of the PA activity elicited by intact cells, secretions, and cellular digests suggests that most of the activity originates on the surface of the cells. The results indicate that the described in vivo effect of AzUR, but not that of PF, on late-stage leukemia, is mediated by the changes in the fibrinolytic potential of the tumor or host cells rather than through the inhibition of the de novo pyrimidine synthesis.

Amides↗
PubMed1980

Virus inhibitory effect of combination of 9-(S)-(2,3-dihydroxypropyl) adenine and 6-azauridine.

Combination of 9-(S)-(2,3-dihydroxypropyl)adenine [(S)-DHPA] and 6-azauridine (AzUrd) is highly active in the selective inhibition of vaccinia virus in chick embryo cell culture. Synergic effect of this combination of compounds was not encountered in HeLa cell culture. Of the 17 analogues related to DHPA studied in this paper, 3 showed medium activity against vaccinia virus, but none of them was as effective as (S)-DHPA in combination with AzUrd.

Adenine↗
PubMed1991

Central depressant effects of N3-substituted 6-azauridines in mice.

Central depressant effects in mice of N3-substituted 6-azauridines (6-AzUd) (1) were examined by intracerebroventricular (i.c.v.) injection. Eleven derivatives including alkyl-, benzyl-, xylyl- and phenylethyl-substitution onto the N3-position of 1 were synthesized and their pharmacological effects were evaluated using hypnotic activity, locomotor activity, motor incoordination and pentobarbital-induced sleep prolongation as indices. Six of 12 compounds showed the hypnotic activity. At a dose of 2 mumol/mouse, the mean sleeping time induced by 1, N3-benzyl-6-AzUd (7), N3-o-xylyl-6-AzUd (8), N3-m-xylyl-6-AzUd (9), N3-p-xylyl-6-AzUd (10) and N3-alpha-phenylethyl-6-AzUd (11) was 14, 11, 45, 12, 9 and 16 min, respectively. These derivatives and N3-beta-phenylethyl-6-AzUd (12) (1.5 mumol/mouse) significantly prolonged pentobarbital-induced (40 mg/kg, i.p.) sleeping time, whereas none of the N3-alkylated derivatives (methyl-, ethyl-, n-propyl-, n-butyl- and allyl-substitution) exerted the hypnotic activity or pentobarbital-induced sleep prolongation. Nucleoside 1 and its xylyl-derivatives (1.5 mumol/mouse) significantly decreased locomotor activity of mice, their effects paralleled the hypnotic activity. These compounds (1.5 mumol/mouse) also produced motor incoordination and potentiated the effect of diazepam-induced motor incoordination. These results indicate that 1 and its benzyl-related derivatives, but not alkyl-derivatives have a depressant effect on the central nervous system.

Animals↗
PubMed1983

6-azauridine triacetate induced hyper beta-alaninemia and its decrease by administration of pyridoxine.

The effect of pyridoxine on 6-azauridine triacetate (6-AzUrd-TA) induced hyper beta-alaninemia was studied in New Zealand albino rabbits in three experiments. In each of the three experiments the animals were administered by gavage: Group 1 (Control), drinking water; Group 2, 6-AzUrd-TA; and Group 3, 6-AzUrD-TA with pyridoxine. While no beta-alanine was found in the control group or in pretreatment samples of the 6-AZUrd-TA and 6-AzUrd-TA + pyridoxine treated animals, high concentrations of this amino acid (191.0 +/- 91.6, 220.2 +/- 116.3, 103.2 +/- 64.4 nmol/ml) were found on the fourth and seventh days of 6-AzUrd-TA treatment with daily doses of 1.0 g/kg and 0.5 g/kg B.W. respectively. The drug induced hyper beta-alaninemia was significantly (p less than or equal to 0.05) reduced in all three experiments by simultaneous pyridoxine administration in daily doses of 50 mg/kg B. W. These results indicate, that daily repeated oral administration of 6-AzUrd-TA causes elevation of serum beta-alanine, which can be partially prevented by oral administration of pyridoxine. They also indirectly support the hypothesis, that 6-AzUrd-TA induced hyper beta-alaninemia is at least partially caused by the inhibition of beta-alanine degrading enzymes, that use pyridoxal phosphate as a coenzyme. Direct measurement of the enzyme activity is planned in our future studies.

Alanine↗