Metabolites of tiazofurin as mediators of its biochemical and pharmacologic effects

  • Gurpreet S. Ahluwalia
  • Hiremagalur N. Jayaram
  • David A. Cooney
Part of the Cancer Treatment and Research book series (CTAR, volume 36)


Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide) was synthesized by the medicinal chemists at ICN as one of a series of potential antiviral compounds [1,2]. In fact, the agent does exhibit a modest to moderate degree of activity against several pathogenic viruses [2,3]. However, at the time, this activity apparently was not judged sufficient to warrant development of the drug towards clinical trials. With the advent of managerial changes at ICN, Dr. Kenneth Paull of the National Cancer Institute made arrangements with Dr. Roland Robins, the chemist who had designed tiazofurin, to screen that compound and a number of related nucleosides for antineoplastic activity. These studies revealed that tiazofurin was effective against the L1210 and P388 leukemias and prompted a broader examination of the compound’s oncolytic potential. Surprisingly, tiazofurin proved to be effective against the subcutaneous Lewis lung carcinoma, a transplantable tumor resistant to the vast majority of standard and experimental chemotherapeutic drugs. Moreover, cures were achieved over a broad range of doses of the compound [4]. It was these studies, then, that prompted the development of tiazofurin toward clinical trials as an antitumor drug.


Nucleoside Diphosphate Kinase Acetate Kinase Adenosine Kinase P388 Leukemia Fast Atom Bombardment Mass Spectrum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fuertes M, Garcia-Lopez T, Garcia-Munoz G, and Stud M: Synthesis of C-glycosyl thiazoles. J Org Chem 41:4076–4077, 1976.CrossRefGoogle Scholar
  2. 2.
    Srivastava PC, Pickering MV, Allen LB, Streeter DG, Campbell MT, Witkowski JT, Sidwell RW, and Robins RK: Synthesis and antiviral activity of certain thiazole C-nucleosides. J Med Chem 20:256–262, 1977.PubMedCrossRefGoogle Scholar
  3. 3.
    Huggins JW, Robins RK, and Canonico PG: Synergistic antiviral effects of ribavirin and the C-nucleoside analogs, tiazofurin and selenazofurin against togaviruses, bunyaviruses, and arenaviruses. Antimicrob Agents Chemother 26:476–480, 1984.PubMedGoogle Scholar
  4. 4.
    Robins RK, Srivastava PC, Narayanan VL, Plowman J, and Paull KD: 2–0-D-ribofuranosylthiazole-4-carboxamide, a novel potential antitumor agent for lung tumors and metastases. J Med Chem 25:107–108, 1982.PubMedCrossRefGoogle Scholar
  5. 5.
    Jayaram HN, Dion RL, Glazer RI, Johns DG, Robins RK, Srivastava PC, and Cooney DA: Initial studies on the mechanism of action of a new oncolytic thiazole nucleoside, 2-β-D-ribofuranosylthiazole-4-carboxamide (NSC 286193). Biochem Parmacol 31:2371–2380, 1982.CrossRefGoogle Scholar
  6. 6.
    Streeter DG and Miller JP: The in vitro inhibition of purine nucleotide biosynthesis by 2-β-D-ribofuranosylthiazole-4-carboxamide. Biochem Biophys Res Commun 103:1409–1415, 1981.PubMedCrossRefGoogle Scholar
  7. 7.
    Lui MS, Faderan MA, Liepnieks JJ, Natsumeda Y, Olah E, Jayaram HN, and Weber G: Modulation of IMP dehydrogenase activity and guanylate metabolism by tiazofurin (2-(3-D-ribofuranosylthiazole-4-carboxamide). J Biol Chem 259:5078–5082, 1984.PubMedGoogle Scholar
  8. 8.
    Jayaram HN, Smith AL, Glazer RI, Johns DG, and Cooney DA: Studies on the mechanism of action of 2-(β-D-ribofuranosylthiazole-4-carboxamide (NSC 286193)-II. Relationship between dose level and biochemical effects in P388 leukemia in vivo. Biochem Pharmacol 31:3839–3845, 1982.PubMedCrossRefGoogle Scholar
  9. 9.
    Streeter DG and Robins RK: Comparative in vitro studies of tiazofurin and a selenazole analog. Biochem Biophys Res Commun 115:544–550, 1983.PubMedCrossRefGoogle Scholar
  10. 10.
    Cooney DA, Jayaram HN, Gebeyehu G, Betts CR, Kelley JA, Marquez VE, and Johns DG: The conversion of 2–β-D-ribofuranosylthiazole-4-carboxamide to an analog of NAD with potent IMP dehydrogenase-inhibitory properties. Biochem Pharmacol 31:2133–2136, 1982.PubMedCrossRefGoogle Scholar
  11. 11.
    Kuttan R, Robins RK, and Saunders PP: Inhibition of inosinate dehydrogenase by metabolites of 2-β-D-ribofuranosylthiazole-4-carboxamide. Biochem Biophys Res Commun 107:862–868, 1982.PubMedCrossRefGoogle Scholar
  12. 12.
    Karle JM, Monks A, and Wolfe RM: Effect of 2–β-D-ribofuranosylthiazole-4-carboxamide on uptake of nucleosides by cultured L1210 cells. Cancer Lett 24:11–18, 1984.PubMedCrossRefGoogle Scholar
  13. 13.
    O’Dwyer PJ, Shoemaker DD, Jayaram HN, Johns DG, Cooney DA, Marsoni S, Malspeis L, Plowman J, Davignon JP, and Davis RD: Tiazofurin: A new antitumor agent. Invest New Drugs 2:79–84, 1984.PubMedGoogle Scholar
  14. 14.
    Trump DL, Tutsch KD, Koeller JM, and Tormey DC: Phase I clinical study with pharmacokinetic analyses of 2-(3-D-ribofuranosylthiazole-4-carboxamide (NSC 286193) administered as a five day infusion. Cancer Res 45:2853–2858, 1985.PubMedGoogle Scholar
  15. 15.
    Saunders PP, Kuttan R, Lai MM, and Robins RK: Action of 2-β-D-ribofuranosyl-thiazole-4-carboxamide (tiazofurin) in Chinese hamster ovary and variant cell lines. Mol Pharmacol 23:534–539, 1983.PubMedGoogle Scholar
  16. 16.
    Spindler CD and Saunders PP: Characterization of tiazofurin phosphorylating activities in CHO cells. Proc Amer Assoc Cancer Res 26:248, 1985.Google Scholar
  17. 17.
    Fridland A and Connelly M: Adenosine kinase deficiency in cultured human lymphoblasts resistant to tiazofurin. Proc Amer Assoc Cancer Res 26:19, 1985.Google Scholar
  18. 18.
    Arnold ST, Jayaram HN, Harper GR, Litterst CL, Malspeis L, DeSouza JJ, Staubus AE, Ahluwalia GS, Wilson YA, and Cooney DA: The disposition and metabolism of tiazofurin in rodents, rabbits, and dogs. Drug Metab Dispos 12:165–173, 1984.PubMedGoogle Scholar
  19. 19.
    Keller PM, McKee SA, and Fyle JA: Cytoplasmic 5’-nucleotidase catalyzes acylovir phosphorylation. J Biol Chem 260:8664–8667, 1985.PubMedGoogle Scholar
  20. 20.
    Cooney DA, Jayaram HN, and Glazer RI: Studies on the mechanism of action of tiazofurin. Metabolism to an analog of NAD with potent IMP dehydrogenase-inhibitory activity. Adv Enzyme Regul 21:271–303, 1983.PubMedCrossRefGoogle Scholar
  21. 21.
    Gebeyehu G, Marquez VE, and Kelley JA: Synthesis of thiazole-4-carboxamide adenine dinucleotide — a powerful inhibitor of IMP dehydrogenase. J Med Chem 26:922–925, 1983.PubMedCrossRefGoogle Scholar
  22. 22.
    Ahluwalia GS, Jayaram HN, Plowman JP, Cooney DA, and Johns DG: Studies on the mechanism of action of 2–0-D-ribofuranosylthiazole 4-carboxamide — V. Factors governing the response of murine tumors to tiazofurin. Biochem Pharmacol 33:1195–1203, 1984.PubMedCrossRefGoogle Scholar
  23. 23.
    Carney DN, Ahluwalia GS, Jayaram HN, Cooney DA, and Johns DG: Relationship between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. J Clin Invest 75:175–182, 1985.PubMedCrossRefGoogle Scholar
  24. 24.
    Jayaram HN, Cooney DA, Glazer RI, Dion RL, and Johns DG: Mechanism of resistance to the oncolytic C-nucleoside 2-β-D-ribofuranosylthiazole-4-carboxamide (NSC 286193). Biochem Pharmacol 31:2557–2560, 1982.PubMedCrossRefGoogle Scholar
  25. 25.
    Cooney DA, Jayaram HN, Ahluwalia GS, Dion RL, Zwelling LA, Kerrigan D, and Johns DG: Pharmacologic and physiologic consequences of resistance to tiazofurin. Proc 13th Intern Congress Chemotheraphy 17; 261/46–261/52, 1983.Google Scholar
  26. 26.
    Jayaram HN: Biochemical mechanisms of resistance to tiazofurin. Adv Enzyme Reg (in press), 1985.Google Scholar
  27. 27.
    Jayaram HN, Pillwein K, Lui MS, Faderan MA, and Weber G: Mechanism of resistance to tiazofurin in hepatoma 3924A. Biochem Pharmacol (in press), 1985.Google Scholar
  28. 28.
    Jayaram HN, Pillwein K, Nichols CR, Hoffman R, and Weber G: Sensitivity to tiazofurin of human normal, and leukemic leukocytes in vitro. J Clin Invest (in press), 1986.Google Scholar
  29. 29.
    Hogeboom GH and Schneider WC: Cytochemical studies VI. The synthesis of diphos-phopyridine nucleotide by liver cell nuclei. J Biol Chem 197:611–620, 1952.PubMedGoogle Scholar
  30. 30.
    Berger NA, Berger SJ, Catino DM, Petzold SJ, and Robins RK: Modulation of nicotinamide adenine dinucleotide and poly (adenosine diphosphoribose) metabolism by the synthetic ’c’ nucleoside analogs, tiazofurin and selenazofurin. J Clin Invest 75:702–709, 1985.PubMedCrossRefGoogle Scholar
  31. 31.
    Liepnieks JJ, Faderan MA, Lui MS, and Weber G: Tiazofurin-induced selective depression of NAD content in hepatoma 3924A. Biochem Biophys Res Commun 122:345–349, 1984.PubMedCrossRefGoogle Scholar
  32. 32.
    Ahluwalia GS, Gebeyehu G, Jayaram HN, Cooney DA, Marquez VE, and Johns DG: Degradation of NAD/TAD analogs by a unique phosphodiesterase from Colon-38 tumor. Proc Amer Assoc Cancer Res 25:343, 1984.Google Scholar
  33. 33.
    Gebeyehu G, Marquez VE, VanCott A, Cooney DA, Kelley JA, Jayaram HN, Ahluwalia GS, Dion RL, Wilson YA, and Johns DG: Ribavirin, tiazofurin, and selenazofurin: Mononucleotides and nicotinamide adenine dinucleotide analogues; synthesis, structure and interactions with IMP dehydrogenase. J Med Chem 28:99–105, 1985.PubMedCrossRefGoogle Scholar
  34. 34.
    Gabriel JL and Plaut GW: Specific site inhibitors of NAD-specific isocitrate dehydrogenase from bovine heart. J Biol Chem 257:8021–8029, 1982.PubMedGoogle Scholar
  35. 35.
    Grage TB, Rochlin DB, Weiss AJ, and Wilson WL: Clinical studies with tubercidin administered after absorption into human erythrocytes. Cancer Res 30:79–81, 1970.PubMedGoogle Scholar
  36. 36.
    Weber G, Natsumeda Y, Lui MS, Faderan MA, Liepnieks JJ, and Elliott WL: Control of enzymic programs and nucleotide pattern in cancer cells by acivicine and tiazofurin. Adv Enz Reg 22:69–93, 1984.CrossRefGoogle Scholar
  37. 37.
    Melink TJ, VonHoff DD, Kuhn JG, Hersh MR, Sternson LA, Patton TF, Siegler R, Boldt DH, and Clark GM: Phase I evaluation and pharmacokinetics of tiazofurin (2–0-D-ribofuranosylthiazole-4-carboxamide, NSC 286193). Cancer Res 45:2859–2865, 1985.PubMedGoogle Scholar
  38. 38.
    Barrio JR, Secrist JA, and Leonard NJ: Fluorescent adenosine and cytidine derivatives. Biochem Biophys Res Commun 46:597–604, 1972.PubMedCrossRefGoogle Scholar
  39. 39.
    Sokoloski J A and Sartorelli AC: Induction of differentiation of HL-60 promyelocytic leukemia cells by inhibitors of IMP dehydrogenase. Proc Amer Asoc Cancer Res 25:42, 1984.Google Scholar

Copyright information

© Martinus Nijhoff Publishers, Boston 1987

Authors and Affiliations

  • Gurpreet S. Ahluwalia
  • Hiremagalur N. Jayaram
  • David A. Cooney

There are no affiliations available

Personalised recommendations