Skip to main content
SpringerLink
Log in

Triazenes and Triazene N-Oxides: Antitumour Action in Animal Tumour Systems

  • Chapter
Triazenes

  • 53 Accesses

Abstract

The wealth of literature relating to the triazenes amounts, according to the Chemical Abstracts Service, to some 1200 papers over the past twenty years, of which many relate to the antitumour action of these compounds. Thus it is necessary to be selective in the choice of topics for a review of this nature. The object therefore is to attempt to show how the in vivo antitumour test results of these compounds have given an insight into their mode of action and the structural requirements for it, and led to the choice of clinical agents. Some significant observations have so far been largely ignored and these will be highlighted. Finally the activity of some triazene N-oxides will be discussed together with their potential application.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. P. Griess, Uber eine neue Klasse organischer Verbindungen in denen Wasserstoff durch Stickstoff vertreten ist, Ann. Chem., 121: 257–280 (1862).

    Article  Google Scholar 

  2. A. Baeyer and C. Jaeger, Ueber die Amide des Diazobenzols, Ber., 8: 148–151 (1875).

    Google Scholar 

  3. H. Druckrey, Specific carcinogenic and teratogenic effects of “indirect” alkylating methyl and ethyl compounds and their dependency on stages of oncogenic development, Xenobiotica, 3: 217–303 (1973).

    Article  Google Scholar 

  4. D.A. Clarke, R.K. Barclay, C.C. Stock and C.S. Rondestvedt, Triazenes as Inhibitors of Mouse Sarcoma 180, Proc. Soc. Exptl. Biol. Med., 90: 484–489 (1955).

    CAS  Google Scholar 

  5. J.H. Burchenal, M.K. Dagg, M. Beyer and C.C. Stock, Chemotherapy of Leukemia VII. Effect of substituted triazenes on transplanted mouse leukemia, Proc. Soc. Expt. Biol. Med., 91: 398–401 (1956).

    CAS  Google Scholar 

  6. H. Foerster and D. Steinhoff, Cytostatic mono- and bis-dialkyl triazenes, South African Pat. 69 04,895, Chem. Abs., 73, 55823 (1970).

    Google Scholar 

  7. Uniroyal Inc., Substituted triazenes as pre-emergent herbicides, Brit. Pat. 1,130,469, Chem. Abs., 70, 19788 (1969).

    Google Scholar 

  8. M. Mazza, G. Pagani, G. Calderara and L. Vicarini, Phytotoxic activity of triazene derivatives. I. 1-Phenyl-3,3-dialkyltriazenes phenyl-substituted with alkyl, halo or nitro groups, Farmaco, Ed. Sci., 28: 846–861 (1973).

    CAS  Google Scholar 

  9. Y.F. Shealy, R.F. Struck, L.B. Holum and J.A. Montgomery, Synthesis of potential anticancer agents. XXIX. 5-Diazoimidazole-4-carboxamide and 5-diazo-v-triazole-4-carboxamide, J. Org. Chem., 26: 2396–2401 (1961).

    Article  CAS  Google Scholar 

  10. J.A. Montgomery, Experimental studies at Southern Research Institute with DTIC (NSC-45388), Cancer Treat. Rept., 60: 125–134 (1976).

    CAS  Google Scholar 

  11. Y.F. Shealy, C.A. Krauth and J.A. Montgomery, Imidazoles. I. Coupling reactions of 5-diazoimidazole-4-carboxamide (NSC-82196), J.Org.Chem., 27: 2150–2154 (1962).

    Article  CAS  Google Scholar 

  12. Y.F. Shealy and C.A. Krauth, Complete inhibition of mouse leukaemia L1210 by 5(or 4)-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4 (or 5)-carboxamide, Nature, 210: 208–209, (1966).

    Article  PubMed  CAS  Google Scholar 

  13. Y.F. Shealy, Triazenylimidazoles and related compounds, Adv. in Med. Oncol. Res. Educ.: Proc. Int. Cancer Congress 12th, Pergamon, Oxford, Vol 5: 49–58 (1978).

    Google Scholar 

  14. D.W. Miles and R.L. Souhami, Chemotherapy of metastatic disease, Bailtière’s Clin. Oncol, 1: 551–573 (1987).

    Google Scholar 

  15. I. Kline, R.J. Woodman, M. Gang and J.M. Venditti, Effectiveness of antileukemia agents in mice inoculated with leukemia L1210 variants resistant to 5-(3,3-dimethyl-1-triafceno)imidazole-4-carboxamide (NSC-45388) or 5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide (NSC-82196), Cancer Chemother. Repts, 55: 9–28 (1971).

    CAS  Google Scholar 

  16. Y.F. Shealy, C.A. Krauth, C.E. Opliger, H.W. Guin and W.R. Laster, Triazenes of phenylbutyric, hydrocinnamic, phenoxyacetic and benzoylglutamic acid derivatives, J. Pharm. Sci., 60: 1192–1198 (1971).

    Article  PubMed  CAS  Google Scholar 

  17. Y.F. Shealy, C.A. O’Dell, J.D. Clayton and C.A. Krauth, Benzene analogues of triazenoimidazoles, J. Pharm. Sci., 60: 1462–1468 (1971).

    Google Scholar 

  18. T.A. Connors, P.M. Goddard, K. Merai, W.C.J. Ross and D.E.V. Wilman, Tumour inhibitory triazenes: structural requirements for an active metabolite, Biochem. Pharmacol., 25: 241–246 (1976).

    Article  PubMed  CAS  Google Scholar 

  19. R.C.S. Audette, T.A. Connors, H.G. Mandel, K. Merai and W.C.J. Ross, Studies on the mechanism of action of the tumour inhibitory triazenes, Biochem. Pharmacol., 22: 1855–1864 (1973).

    Article  PubMed  CAS  Google Scholar 

  20. G.J. Hatheway, C. Hansen, K.H. Kim, S.R. Milstein, C.L. Schmidt and R.N. Smith, Antitumor 1-(X-aryl)-3,3-dialkyltriazenes. I. Quantitative structure-activity relationships vs. L1210 leukemia in mice, J. Med. Chem., 21: 563–574 (1978).

    Article  PubMed  CAS  Google Scholar 

  21. C. Hansch, G.J. Hatheway, F.R. Quinn and N. Greenberg, Antitumor 1-(X-aryl)-3,3-dialkyltriazenes. 2. On the role of correlation analysis in decision making in drug modification. Toxicity quantitative structure-activity relationships of 1-(X-phenyl)-3,3-dialkyltriazenes in mice, J. Med. Chem., 21: 574–577 (1978).

    Article  PubMed  CAS  Google Scholar 

  22. D. Farquhar and J. Benvenuto, 1-Aryl-3,3-dimethyltriazenes: potential central nervous system active analogues of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) J. Med. Chem., 27: 1723–1727 (1984).

    Article  PubMed  CAS  Google Scholar 

  23. V.A. Levin, Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability, J. Med.Chem., 23: 682–684 (1980).

    Article  PubMed  CAS  Google Scholar 

  24. D.E.V. Wilman, N.J. Bradley and S.G. Richardson, Astrocytoma xenografts in the choice of a second-generation triazene, Brit. J. Cancer, 50: 277 (1984).

    Google Scholar 

  25. G.J. Atwell, B.F. Cain and W.A. Denny, Potential antitumor agents. 22. Latentiated congeners of the 4’-(9-acridinyl-amino)methanesulfonanilides, J. Med.Chem., 20: 520–526 (1977).

    Article  PubMed  CAS  Google Scholar 

  26. G. Abel, T.A. Connors, P. Goddard, H. Hoellinger, N.-H. Nam, L. Pichat, W.C.J. Ross and D.E.V. Wilman, Cytotoxic sulphonamides designed for selective deposition in malignant tissues, Europ. J. Cancer, 11: 787–793 (1975).

    Article  CAS  Google Scholar 

  27. A.J. Lin and T.L. Loo, Synthesis and antitumor activity of halogen-substituted 4-(3,3-dimethyl-1-triazeno)quinolines, J. Med. Chem., 21: 268–272 (1978).

    Article  PubMed  CAS  Google Scholar 

  28. B.S. Ashby, pH Studies in human malignant tumours, Lancet, ii: 312–315 (1966).

    Article  Google Scholar 

  29. C.D. Stevens, M.A. Wagner, P.M. Quinlin and A.M. Kock, Localization of sulfapyrazine in cancer tissue on glucose injection, Cancer Res., 12: 634–639 (1952).

    PubMed  CAS  Google Scholar 

  30. G. Abel, T.A. Connors, W.C.J. Ross, N.-H. Nam, H. Hoellinger and L. Pichat, The selective concentration of sulphadiazine and related compounds in malignant tissue, Eur. J. Cancer, 9: 49–54 (1973).

    Article  PubMed  CAS  Google Scholar 

  31. N. Calvert, T.A. Connors and W.C.J. Ross, Aryl-2-halogenoalkylamines XXV. Derivatives of sulphanilamide designed for selective deposition in neoplastic tissue. Europ. J. Cancer, 4: 627–636 (1968).

    Article  CAS  Google Scholar 

  32. S.M. Sieber and R.A. Adamson, Selection of carriers for alkylating moieties to increase their antitumor specificity, Cancer Treatment Rep., 60: 217–219 (1976).

    CAS  Google Scholar 

  33. R.E. Counsell, P. Pocha, J.O. Morales and W.H. Beierwaltes, Tumor localizing agents III. Radioiodinated quinoline derivatives, J. Pharm. Sci., 56: 1042–1044 (1967).

    Article  PubMed  CAS  Google Scholar 

  34. E. Bonmassar, A. Bonmassar, S. Vadlamudi and A. Goldin, Immunological alteration of leukemic cells in vivo after treatment with an antitumor drug, Proc. Natl. Acad. Sci. U.S., 66: 1089–1095 (1970).

    Article  CAS  Google Scholar 

  35. F.A. Schmid and D.J. Hutchison, Decrease in oncogenic potential of L1210 leukemia by triazenes, Cancer Res., 33: 2161–2165 (1973).

    PubMed  CAS  Google Scholar 

  36. A. Nicolin, F. Spreafico, E. Bonmassar and A. Goldin, Antigenic changes of L5178Y lymphoma after treatment with 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide in vivo, J. Nat. Cancer Inst., 56: 89–93 (1976).

    PubMed  CAS  Google Scholar 

  37. A. Nicolin, M. Cavalli, A. Missiroli and A. Goldin, Immunogenicity induced in vivo by DIC in relatively non-immunogenic leukemias, Europ. J. Cancer, 13: 235–239 (1977).

    Article  CAS  Google Scholar 

  38. T. Giraldi, A.M. Guarino, C. Nisi and G. Sava, Antitumor and antimetastatic effects of benzenoid triazenes in mice bearing Lewis lung carcinoma, Pharmacol. Res. Commun., 12: 1–11 (1980).

    Article  PubMed  CAS  Google Scholar 

  39. D.J. Kohlsmith, K. Vaughan and S.J. Luner, Triazene metabolism. III. In vitro cytotoxicity towards M21 cells and in vivo antitumor activity of the proposed metabolites of the antitumor 1-aryl-3,3-dimethyltriazenes, Can.J.Physiol.Pharmacol., 62: 396–402 (1984).

    Article  PubMed  CAS  Google Scholar 

  40. K. Vaughan, Y. Tang, G. Llanos, J.K. Horton, R.J. Simmonds, J.A. Hickman and M.F.G. Stevens, Studies of the mode of action of anti-tumor triazenes and triazines. 6. 1-Aryl-3-hydroxymethyl-1-methyltriazenes: synthesis, chemistry and anti-tumor properties, J. Med. Chem., 27: 357–363 (1984).

    Article  PubMed  CAS  Google Scholar 

  41. L.M. Cameron, R.J. LaFrance, C.M. Hemes, K. Vaughan, R. Rajaraman, D.C. Chubb and P.M. Goddard, Triazene metabolism IV. Derivatives of hydroxymethyltriazenes: potential prodrugs for the active metabolites of the antitumour triazene, DTIC, Anti-Cancer Drug Des., 1: 27–36, (1985).

    CAS  Google Scholar 

  42. K. Vaughan, K.U.K. Gamage Nicholas, R.D. Singer, M. Roy and N.W. Gibson, Triazene metabolism. VI. 3-Azidomethyl-3-alkyl-1-aryltriazenes, a new class of antitumour triazene with potential pro-drug applications, Anti-Cancer Drug Des., 2: 279–287 (1987).

    CAS  Google Scholar 

  43. K. Vaughan, H.W. Manning, M.P. Merrin and D.L. Hooper, Open chain nitrogen compounds. Part XIII. 1-Aryl-3-arylthio-methyl-3-methyltriazenes and 3-(arylazo)-1,3-thiazolidines, Can. J. Chem., 66: 2487–2491 (1988).

    Article  CAS  Google Scholar 

  44. J. Hey, E. Rosa and L. Fernandes, Triazene drug metabolites. Part 5. A simple direct synthesis of 3-alkoxymethyl- and 3-alkylthiomethyl-1-aryl-3-alkyltriazenes from l-aryl-3-hydroxymethyl-3-alkyltriazenes, J. Chem. Research (S), 264–265 (1987).

    Google Scholar 

  45. F.K. Hess, P.A. Stewart, G. Possanza and K. Freter, Immunosupressive 1-phenyl-3-hydroxy-3-methyltriazenes, Ger. Patent, 2,208,368, Chem. Abs., 79: 146271 (1973).

    Google Scholar 

  46. J.L. Miesel, 3,3-Dialkyl-l-(substitutedphenyl)triazene-1-oxides, U.S. Patent, 3,989,680 (1976).

    Google Scholar 

  47. J.L. Miesel, 3-Aryltriazene 1-oxides for treating inflammatory diseases, U.S. Patent, 3,962,434 (1976).

    Google Scholar 

  48. S. Neidle and D.E.V. Wilman, Unpublished data.

    Google Scholar 

  49. K. Freter, F. Hess and K. Grozinger, Acylierung von Hydroxy-phenyl-triazenes, eine neuartige Umlagerung, Ann.Chem., 811–820 (1973).

    Google Scholar 

  50. A.G. Giumanini, L. Lassiani, C. Nisi, A. Petrie and B. Starovnik, The structure of aryldialkyltriazene N-oxides, Bull.Chem.Soc.Jpn., 56: 1887–1888 (1983).

    Article  CAS  Google Scholar 

  51. R. Kuroda and D.E.V. Wilman, 3-(4-Carbamoylphenyl)-1-methyltriazene 1-oxide, Acta Cryst., C41: 1543–1545 (1986).

    Google Scholar 

  52. S. Neidle, G.D. Wehster, R. Kuroda and D.E.V. Wilman, Synthesis and structure of 3-(4-carbamoylphenyl)-1,3-dimethyltriazene 1-oxide, Acta Cryst., C43: 674–676 (1987).

    CAS  Google Scholar 

  53. D.E.V. Wilman and P.M. Goddard, Triazene N-oxides. 2. Synthesis and antitumour activity of some triazene 1-oxides, Prog. in Pharmacol. Clin. Pharmacol., in press.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Development Section Institute of Cancer Research, Cancer Research Campaign Laboratory, Cotswold Road, Sutton Surrey, SM2 5NG, UK

    Derry E. V. Wilman

Authors
  1. Derry E. V. Wilman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Istituto di Farmacologia, Università di Trieste, 34127, Trieste, Italy

    Tullio Giraldi

  2. Toxicology Unit, Medical Research Council, Woodmansterne Road, SM5 4EF, Carshalton, Surrey, UK

    Thomas A. Connors

  3. Divisione di Oncologia Medica, Ospedale S. Maria della Misericordia, 33100, Udine, Italy

    Giuseppe Cartei

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Springer Science+Business Media New York

About this chapter

Cite this chapter

Wilman, D.E.V. (1990). Triazenes and Triazene N-Oxides: Antitumour Action in Animal Tumour Systems. In: Giraldi, T., Connors, T.A., Cartei, G. (eds) Triazenes. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3832-5_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-3832-5_3

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6710-9

  • Online ISBN: 978-1-4615-3832-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation