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. 1987 Oct;31(10):1535–1541. doi: 10.1128/aac.31.10.1535

Novel pyrazolo[3,4-d]pyrimidine nucleoside analog with broad-spectrum antiviral activity.

D F Smee 1, P A McKernan 1, L D Nord 1, R C Willis 1, C R Petrie 1, T M Riley 1, G R Revankar 1, R K Robins 1, R A Smith 1
PMCID: PMC174985  PMID: 3435102

Abstract

A novel nucleoside analog, 4(5H)-oxo-1-beta-D- ribofuranosylpyrazolo[3,4-d]pyrimidine-3-thiocarboxamide (N10169), was evaluated in cell culture and in animals for antiviral activity against DNA and RNA viruses. The compound was highly active against strains of adeno-, vaccinia, influenza B, paramyxo-, picorna-, and reoviruses, with 50% inhibition of virus-induced cytopathology at 1 to 10 microM. Lesser or no antiviral effects were observed against herpes simplex, cytomegalo-, corona-, influenza A, vesicular stomatitis, and visna viruses. Drug potency against certain viruses was highly cell line dependent (N10169 was highly active in HeLa cells but was much less potent in Vero cells). This was correlated, in part, to differences in levels of adenosine kinase activity in these cell lines, since adenosine kinase appears to phosphorylate N10169 to its active form. N10169 was inhibitory to proliferating cells at antiviral concentrations, whereas stationary-phase monolayers tolerated higher concentrations (less than or equal to 100 microM). Exogenous uridine was able to reverse the virus-inhibitory effects of the compound, leading to the discovery that N10169 5'-monophosphate is a potent inhibitor of cellular orotidylate decarboxylase. N10169 was evaluated in mice that were infected intraperitoneally with banzi virus or inoculated intranasally with influenza B virus, and in hamsters that were infected intranasally with vaccinia virus. In each model, intraperitoneal injection of N10169 (100 to 300 mg/kg per day for 7 days) twice daily was ineffective, whereas intraperitoneal injection of ribavirin showed some benefit in the influenza B and banzi virus infection models.

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Selected References

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  1. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  2. Chen S. F., Ruben R. L., Dexter D. L. Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbo xylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Res. 1986 Oct;46(10):5014–5019. [PubMed] [Google Scholar]
  3. Cottam H. B., Petrie C. R., McKernan P. A., Goebel R. J., Dalley N. K., Davidson R. B., Robins R. K., Revankar G. R. Synthesis and biological activity of certain 3,4-disubstituted pyrazolo[3,4-d]pyrimidine nucleosides. J Med Chem. 1984 Sep;27(9):1119–1127. doi: 10.1021/jm00375a006. [DOI] [PubMed] [Google Scholar]
  4. Durr F. E., Lindh H. F., Forbes M. Efficacy of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide against influenza virus infections in mice. Antimicrob Agents Chemother. 1975 May;7(5):582–586. doi: 10.1128/aac.7.5.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fyfe J. A., Miller R. L., Krenitsky T. A. Kinetic properties and inhibition of orotidine 5'-phosphate decarboxylase. Effects of some allopurinol metabolites on the enzyme. J Biol Chem. 1973 Jun 10;248(11):3801–3809. [PubMed] [Google Scholar]
  6. Gebeyehu G., Marquez V. E., Van Cott A., Cooney D. A., Kelley J. A., Jayaram H. N., Ahluwalia G. S., Dion R. L., Wilson Y. A., Johns D. G. Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogues. Synthesis, structure, and interactions with IMP dehydrogenase. J Med Chem. 1985 Jan;28(1):99–105. doi: 10.1021/jm00379a018. [DOI] [PubMed] [Google Scholar]
  7. Hershfield M. S., Snyder F. F., Seegmiller J. E. Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes. Science. 1977 Sep 23;197(4310):1284–1287. doi: 10.1126/science.197600. [DOI] [PubMed] [Google Scholar]
  8. Ives D. H., Durham J. P., Tucker V. S. Rapid determination of nucleoside kinase and nucleotidase activities with tritium-labeled substrates. Anal Biochem. 1969 Apr 4;28(1):192–205. doi: 10.1016/0003-2697(69)90170-5. [DOI] [PubMed] [Google Scholar]
  9. Jones M. E., Kavipurapu P. R., Traut T. W. Orotate phosphoribosyltransferase: orotidylate decarboxylase (Ehrlich ascites cell). Methods Enzymol. 1978;51:155–167. doi: 10.1016/s0076-6879(78)51023-9. [DOI] [PubMed] [Google Scholar]
  10. Karle J. M., Anderson L. W., Cysyk R. L. Effect of plasma concentrations of uridine on pyrimidine biosynthesis in cultured L1210 cells. J Biol Chem. 1984 Jan 10;259(1):67–72. [PubMed] [Google Scholar]
  11. Kemp A. J., Lyons S. D., Christopherson R. I. Effects of acivicin and dichloroallyl lawsone upon pyrimidine biosynthesis in mouse L1210 leukemia cells. J Biol Chem. 1986 Nov 15;261(32):14891–14895. [PubMed] [Google Scholar]
  12. Kirsi J. J., North J. A., McKernan P. A., Murray B. K., Canonico P. G., Huggins J. W., Srivastava P. C., Robins R. K. Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent. Antimicrob Agents Chemother. 1983 Sep;24(3):353–361. doi: 10.1128/aac.24.3.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Knight V., Wilson S. Z., Alling D. W., Moore R. V., Longoria R. M. Lack of interference of guanosine with ribavirin aerosol treatment of influenza A infection in mice. Antimicrob Agents Chemother. 1981 Oct;20(4):477–480. doi: 10.1128/aac.20.4.477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Malinoski F., Stollar V. Inhibitors of IMP dehydrogenase prevent sindbis virus replication and reduce GTP levels in Aedes albopictus cells. Virology. 1981 Apr 30;110(2):281–289. doi: 10.1016/0042-6822(81)90060-x. [DOI] [PubMed] [Google Scholar]
  15. Petrie C. R., 3rd, Revankar G. R., Dalley N. K., George R. D., McKernan P. A., Hamill R. L., Robins R. K. Synthesis and biological activity of certain nucleoside and nucleotide derivatives of pyrazofurin. J Med Chem. 1986 Feb;29(2):268–278. doi: 10.1021/jm00152a016. [DOI] [PubMed] [Google Scholar]
  16. Rada B., Altanerová V. Virus-inhibitory activity of 6-azauridine dependent on cell-free extracts containing uridine kinase. I. Inhibition of plaque-formation. Acta Virol. 1970 Nov;14(6):425–434. [PubMed] [Google Scholar]
  17. Sidwell R. W., Huffman J. H., Khare G. P., Allen L. B., Witkowski J. T., Robins R. K. Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 1972 Aug 25;177(4050):705–706. doi: 10.1126/science.177.4050.705. [DOI] [PubMed] [Google Scholar]
  18. Sidwell R. W., Huffman J. H. Use of disposable micro tissue culture plates for antiviral and interferon induction studies. Appl Microbiol. 1971 Nov;22(5):797–801. doi: 10.1128/am.22.5.797-801.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Smee D. F., Matthews T. R. Metabolism of ribavirin in respiratory syncytial virus-infected and uninfected cells. Antimicrob Agents Chemother. 1986 Jul;30(1):117–121. doi: 10.1128/aac.30.1.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sundquist B., Larner E. Phosphonoformate inhibition of visna virus replication. J Virol. 1979 Jun;30(3):847–851. doi: 10.1128/jvi.30.3.847-851.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Willis R. C., Carson D. A., Seegmiller J. E. Adenosine kinase initiates the major route of ribavirin activation in a cultured human cell line. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3042–3044. doi: 10.1073/pnas.75.7.3042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Willis R. C., Seegmiller J. E. The inhibition by 6-diazo-5-oxo-l-norleucine of glutamine catabolism of the cultured human lymphoblast. J Cell Physiol. 1977 Dec;93(3):375–382. doi: 10.1002/jcp.1040930308. [DOI] [PubMed] [Google Scholar]
  23. Wray S. K., Gilbert B. E., Noall M. W., Knight V. Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis. Antiviral Res. 1985 Feb;5(1):29–37. doi: 10.1016/0166-3542(85)90012-9. [DOI] [PubMed] [Google Scholar]

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