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International Journal of Molecular... Mar 20216-Azauridine (6-AZA), a pyrimidine nucleoside analogue, is known to exhibit both antitumor and antiviral activities. Although 6-AZA was discovered more than 60 years...
6-Azauridine (6-AZA), a pyrimidine nucleoside analogue, is known to exhibit both antitumor and antiviral activities. Although 6-AZA was discovered more than 60 years ago, the cellular effects of this compound are yet to be elucidated. Here, we report that 6-AZA regulates autophagy-mediated cell death in various human cancer cells, where 6-AZA treatment activates autophagic flux through the activation of lysosomal function. Furthermore, 6-AZA exhibited cytotoxicity in all cancer cells studied, although the mechanisms of action were diverse. In H460 cells, 6-AZA treatment induced apoptosis, and the extent of the latter could be reduced by treatment with chloroquine (CQ), a lysosomal inhibitor. However, 6-AZA treatment resulted in cell cycle arrest in H1299 cells, which could not be reversed by CQ. The cytotoxicity associated with 6-AZA treatment could be linearly correlated to the degree of autophagy-mediated cell death. In addition, we demonstrated that the cytotoxic effect of 6-AZA was dependent on AMPK and p53. These results collectively indicate that autophagy-mediated cell death triggered by 6-AZA contributes to its antitumor effect.
Topics: AMP-Activated Protein Kinase Kinases; Antineoplastic Agents; Apoptosis; Autophagic Cell Death; Autophagy; Azauridine; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chloroquine; Drug Synergism; Humans; Lysosomes; Neoplasms; Protein Kinases; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 33799444
DOI: 10.3390/ijms22062947 -
The Journal of Antibiotics Jul 2019The emergence of new drug-resistant strains of bacteria necessitates the development of principally new antibacterial agents. One of the novel classes of antibacterial...
The emergence of new drug-resistant strains of bacteria necessitates the development of principally new antibacterial agents. One of the novel classes of antibacterial agents is nucleoside analogs. We have developed a fast and simple one-pot method for preparation of α- and β-anomers of 5-modified 6-aza- and 2-thio-6-aza-2'-deoxyuridine derivatives in high yields. 2-Thio derivatives demonstrated moderate activity against Mycobacterium smegmatis (MIC = 0.2-0.8 mM), Staphylococcus aureus (MIC = 0.03-0.9 mM) and some other Gram-positive bacteria. 2'-Deoxy-2-thio-5-phenyl-6-azauridine (2b) effectively suppressed the growth of Gram-negative bacteria Pseudomonas aeruginosa ATCC 27853 (MIC = 0.03 mM)-the one that causes diseases difficult to treat due to high resistance to antibiotics. 5'-Monophosphates of compounds 2a, b and 3a, b were docked into a binding site of Mycobacterium tuberculosis flavin-dependent thymidylate synthase (ThyX) enzyme. The molecular modeling demonstrates the possibility of binding of the 5-modified 2-thio-6-aza-2'-deoxyuridine 5'-monophosphates within the active site of the enzyme and thereby inhibiting the growth of the bacteria.
Topics: Animals; Anti-Bacterial Agents; Azauridine; Catalytic Domain; Cell Line; Cell Survival; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Mycobacterium smegmatis; Mycobacterium tuberculosis; Pseudomonas aeruginosa; Staphylococcus aureus; Thymidylate Synthase
PubMed: 30792519
DOI: 10.1038/s41429-019-0158-z -
Cancer Research Sep 1963
Review
Topics: Azauridine; Idoxuridine; Metabolism; Neoplasms; Nucleosides; Pharmacology
PubMed: 14070380
DOI: No ID Found -
Retrovirology Mar 2016BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the...
BACKGROUD
BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface.
RESULTS
Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination.
CONCLUSION
Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction.
Topics: Anti-HIV Agents; Antigens, CD; Azauridine; Drug Evaluation, Preclinical; GPI-Linked Proteins; HIV-1; HeLa Cells; Human Immunodeficiency Virus Proteins; Humans; Thiouridine; Viral Regulatory and Accessory Proteins
PubMed: 26935098
DOI: 10.1186/s12977-016-0247-z -
European Journal of Clinical... Mar 1972
Clinical Trial Review
Topics: Adult; Animals; Antiviral Agents; Azauridine; Child, Preschool; Clinical Trials as Topic; Female; Herpes Simplex; Humans; Leukemia; Male; Middle Aged; Mycosis Fungoides; Placebos; Psoriasis; Smallpox; Tuberculin Test
PubMed: 4570456
DOI: 10.1007/BF00562501 -
Australian and New Zealand Journal of... Aug 1973
Review
Topics: Allopurinol; Anemia, Pernicious; Animals; Azauridine; Carboxy-Lyases; Fatty Liver; Female; Humans; Infant, Newborn; Jaundice, Neonatal; Lipids; Metabolic Diseases; Metabolism, Inborn Errors; Milk; Myocardial Infarction; Ornithine Carbamoyltransferase; Orotic Acid; Pentosyltransferases; Pregnancy; Uric Acid
PubMed: 4586514
DOI: 10.1111/j.1445-5994.1973.tb03117.x -
Advances in Experimental Medicine and... 1977
Topics: Adenine; Adenine Phosphoribosyltransferase; Adenosine; Azauridine; DNA; HeLa Cells; Hypoxanthine Phosphoribosyltransferase; Kinetics; Pentosyltransferases; Purines
PubMed: 855744
DOI: 10.1007/978-1-4684-3285-5_24 -
ACS Omega Dec 2020Uridine (U) mimetics are sought after as tools for biochemical and pharmacological studies. Previously, we have identified recognition patterns of U by proteins. Here,...
Uridine (U) mimetics are sought after as tools for biochemical and pharmacological studies. Previously, we have identified recognition patterns of U by proteins. Here, we targeted the characterization of uridine mimetics-cyanuryl-ribose (CR), barbituryl-ribose (BR), and 6-azauridine (AU)-with a view to identify analogs with potentially more binding interactions than U with target biomolecules. We found that CR, BR, and AU retain selective U's natural H-bonds with adenosine vs guanosine. CR/AU and BR were 100- and 10,000-fold more acidic, respectively, than U. Under physiological pH, 54, 51, and 77% of CR, AU, and BR molecules, respectively, are ionized vs 13% for U. The electron-rich nature of CR and BR vs U was reflected by their C NMR chemical shifts and ε values. CR/AU and BR prefer conformation (up to 73%) vs U (56%). Unlike U that prefers conformation around exocyclic methylol (48%), CR/AU and BR prefer both and rotamers. In conclusion, replacement of uridine's C6 by N or carbonyl, or C5-C6 by an amide, results in significant changes in U's ionization, electron density, conformation, base-stacking, etc., leading to potentially tighter binding than U with a target protein or nucleic acid and potential use for various biochemical and pharmacological applications.
PubMed: 33324842
DOI: 10.1021/acsomega.0c04788 -
The American Journal of the Medical... 1977Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion... (Review)
Review
Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. It is inherited as an autosomal recessive trait with a worldwide distribution. The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.
Topics: Animals; Azauridine; Bone and Bones; Cystathionine; Cystathionine beta-Synthase; Folic Acid; Homocysteine; Homocystinuria; Humans; Intellectual Disability; Lens, Crystalline; Metabolism, Inborn Errors; Methionine; Pyridoxine; Schizophrenia; Seizures; Thromboembolism; Vitamin B 12
PubMed: 324277
DOI: No ID Found -
Annals of the New York Academy of... Mar 19776-Azauridine (AzUrd) is a broad-spectrum antimetabolite that inhibits both DNA and RNA virus multiplication. Prior work indicated that several AzUrd-sensitive viruses...
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.
Topics: Antiviral Agents; Azauridine; Orotic Acid; Pyrimidines; Viruses
PubMed: 280143
DOI: 10.1111/j.1749-6632.1977.tb21977.x