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Journal of Molecular Biology Mar 1973
Topics: Azauridine; Binding Sites; Crystallography; Nucleic Acid Conformation; Uridine
PubMed: 4713299
DOI: 10.1016/0022-2836(73)90534-2 -
European Journal of Biochemistry Nov 1982Brief exposure to 6-azauridine stimulates the production of carbamoyl phosphate for de novo pyrimidine biosynthesis in vitro in slices of haematopoietic spleen from...
Enhancement of intracellular 5-phosphoribosyl 1-pyrophosphate levels as a major factor in the 6-azauridine-induced stimulation of carbamoyl phosphate synthesis in mouse spleen slices.
Brief exposure to 6-azauridine stimulates the production of carbamoyl phosphate for de novo pyrimidine biosynthesis in vitro in slices of haematopoietic spleen from anaemic mice (preceding paper). In studies of the underlying mechanism for this response we turned our attention to changes in the level of substrates and effectors for carbamoyl-phosphate synthetase II. Intermediates of the orotic acid pathway and 6-azauridine had little effect on the synthetase activity in vitro. 6-Azauridine 5'-monophosphate (6-AzaUMP) stimulated synthetase II, possibly in an allosteric manner. However, in view of the potency as an activator and the tissue levels, 6-azaUMP may be only partially responsible for the stimulation. Adenine nucleotide levels in the tissue showed only minor changes after brief exposure (15 min) to 6-azauridine. The level of UTP and UDP, potent inhibitors for synthetase II, showed no significant change. The level of 5-phosphoribosyl 1-pyrophosphate (PPRibP), a potent positive effector for the synthetase II, showed a more than 1.5-fold increase after 15 min. The relative importance of these factors was evaluated by assay of the synthetase, partially purified from mouse spleen, under simulated conditions in vitro. The results indicated that the enhanced level of PPRibP played a major role in increasing the production of carbamoyl phosphate. In Ehrlich ascites cells in vitro, where 6-azauridine did not increase carbamoyl phosphate production, the basal PPRibP level was high (range over 0.1 mM) and the changes in the level, brought about by the analogue, were relatively small.
Topics: Animals; Azauridine; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); In Vitro Techniques; Kinetics; Ligases; Male; Mice; Mice, Inbred Strains; Pentosephosphates; Phosphoribosyl Pyrophosphate; Spleen
PubMed: 6185335
DOI: 10.1111/j.1432-1033.1982.tb07010.x -
The Journal of Pharmacy and Pharmacology Aug 1966
Comparative Study
Topics: Acetylcholine; Animals; Antimetabolites; Barium; Electric Stimulation; Electrophysiology; Guinea Pigs; Histamine; Ileum; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Nicotine; Nucleosides; Papaverine
PubMed: 4381855
DOI: 10.1111/j.2042-7158.1966.tb07917.x -
Changes in preference for NaCl following administration of 6-azauridine and 6-azauridine triacetate.Pharmacology and Therapeutics in... 1975Preliminary evidence in man has suggested that 6-azauridine triacetate (6-AzUrdTA) might adversely affect taste acuity. The production of measurable serum concentrations...
Preliminary evidence in man has suggested that 6-azauridine triacetate (6-AzUrdTA) might adversely affect taste acuity. The production of measurable serum concentrations of homocysteine in rabbits treated with 6-AzUrdTA further suggested a mechanism for the possible adverse effects of this drug on taste, since administration of other thiol-containing drugs in man and animals had been shown to decrease taste acuity. Since changes in preferences for NaCl solutions have been shown to reflect changes in taste acuity in the rat, preference for NaCl solutions in rats treated with 6-AzUrdTA were measured in a two-bottle test. Detection and recognition thresholds were also measured in patients with scleroderma before and after the administration of 6-AzUrdTA. Serum copper and zinc concentrations were measured in both rats and man. Rats given 6-AzUrdTA exhibited a significantly greater intake of 0.30-M NaCl than control rats, who avoided this solution. This change was accompanied by a significant decrease in serum zinc concentrations. No significant changes in taste acuity occurred in the patients. These data suggest that administration of 6-AzUrdTA affects taste acuity in rats either through the addition of thiols or the depletion of zinc.
Topics: Administration, Oral; Adult; Animals; Azauridine; Copper; Differential Threshold; Female; Gastric Lavage; Humans; Injections, Intraperitoneal; Male; Middle Aged; Rats; Scleroderma, Systemic; Sodium Chloride; Spectrophotometry, Atomic; Taste; Zinc
PubMed: 1054856
DOI: No ID Found -
Teratology Aug 1971
Topics: Abnormalities, Drug-Induced; Animals; Female; Pregnancy; Rats; Triazines; Uracil
PubMed: 5109584
DOI: 10.1002/tera.1420040304 -
MMW, Munchener Medizinische... Sep 1975Pyrimidine synthesis and its regulation are presented. Among the disorders of human pyrimidine metabolism, hereditary orotic aciduria and that produced by drugs play the... (Review)
Review
Pyrimidine synthesis and its regulation are presented. Among the disorders of human pyrimidine metabolism, hereditary orotic aciduria and that produced by drugs play the principal role. A rise in renal excretion of orotic acis is also observed when ornithine transcarbamylase activity is lacking. The importance of "orotic aciduria with partial response to folic acid" in pyrimidine metabolism is still not clear. Close relationship between the formation of pyrimidine and purine nucleotides must be assumed, because both enter into the synthesis of nucleic acid, for the greatest part in approximately equimolecular amounts. Possibly 5-phosphoribosyl-1-pyrophosphate plays an important part.
Topics: Allopurinol; Azauridine; Chemical Phenomena; Chemistry; Cytidine; Folic Acid; Humans; Infant; Male; Ornithine Carbamoyltransferase; Orotic Acid; Phosphoribosyl Pyrophosphate; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrimidine Nucleotides; Pyrimidines; Uridine
PubMed: 810667
DOI: No ID Found -
Chemotherapy 1980Combination 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...
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.
Topics: Adenine; Antiviral Agents; Azauridine; Drug Synergism; HeLa Cells; Humans; Vaccinia virus
PubMed: 6153950
DOI: 10.1159/000237903 -
Experientia Jan 1968
Topics: Abnormalities, Drug-Induced; Animals; Antimetabolites; Brain; Brain Chemistry; Chick Embryo; Chromatography, Paper; Nervous System Diseases; Nucleosides; Organ Size; Uracil
PubMed: 5694247
DOI: 10.1007/BF02136788 -
Nature Apr 1973
Topics: Models, Molecular; Nucleic Acid Conformation; Orotidine-5'-Phosphate Decarboxylase; Uracil Nucleotides; Uridine Kinase; Uridine Monophosphate
PubMed: 4621097
DOI: 10.1038/242610a0 -
Antimicrobial Agents and Chemotherapy Jun 2014No antiviral therapies are available for the tick-borne flaviviruses associated with hemorrhagic fevers: Kyasanur Forest disease virus (KFDV), both classical and the...
No antiviral therapies are available for the tick-borne flaviviruses associated with hemorrhagic fevers: Kyasanur Forest disease virus (KFDV), both classical and the Alkhurma hemorrhagic fever virus (AHFV) subtype, and Omsk hemorrhagic fever virus (OHFV). We tested compounds reported to have antiviral activity against members of the Flaviviridae family for their ability to inhibit AHFV replication. 6-Azauridine (6-azaU), 2'-C-methylcytidine (2'-CMC), and interferon alpha 2a (IFN-α2a) inhibited the replication of AHFV and also KFDV, OHFV, and Powassan virus. The combination of IFN-α2a and 2'-CMC exerted an additive antiviral effect on AHFV, and the combination of IFN-α2a and 6-azaU was moderately synergistic. The combination of 2'-CMC and 6-azaU was complex, being strongly synergistic but with a moderate level of antagonism. The antiviral activity of 6-azaU was reduced by the addition of cytidine but not guanosine, suggesting that it acted by inhibiting pyrimidine biosynthesis. To investigate the mechanism of action of 2'-CMC, AHFV variants with reduced susceptibility to 2'-CMC were selected. We used a replicon system to assess the substitutions present in the selected AHFV population. A double NS5 mutant, S603T/C666S, and a triple mutant, S603T/C666S/M644V, were more resistant to 2'-CMC than the wild-type replicon. The S603T/C666S mutant had a reduced level of replication which was increased when M644V was also present, although the replication of this triple mutant was still below that of the wild type. The S603 and C666 residues were predicted to lie in the active site of the AHFV NS5 polymerase, implicating the catalytic center of the enzyme as the binding site for 2'-CMC.
Topics: Amino Acid Substitution; Antiviral Agents; Cell Line; Cytidine; Cytopathogenic Effect, Viral; Drug Resistance, Viral; Flavivirus; Hemorrhagic Fevers, Viral; Humans; Models, Molecular; Mutation; Tick-Borne Diseases; Virus Replication
PubMed: 24663025
DOI: 10.1128/AAC.02393-14