Skip to main content
SpringerLink
Log in

Dichlorobis(cycloalkylamine)platinum(II) complexes structure activity relationship on the human MDA-MB-231 breast cancer cell line

Dichlorobis(cycloalkylamin)platin(II)-Komplexe. Struktur — Wirkungsbeziehungen an der menschlichen MDA-MB-231 Brustkrebszellinie

  • Organische Chemie Und Biochemie
  • Published:
Monatshefte für Chemie / Chemical Monthly Aims and scope Submit manuscript

Summary

The syntheses of dichlorobis(cycloalkylamine)platinum(II) complexes withcis andtrans cycloalkylamine ligands [cis-PtCl2(C3H5NH2)2 tocis-PtCl2(C8H15NH2)2 (3–8) andtrans-PtCl2(C7H13NH2)2 (9) andtrans-PtCl2(C8H15NH2)2 (10)] are described. The distinction betweencis andtrans isomers was achieved by1H-NMR spectroscopy. The antitumor activity was determined on the cell proliferation of the human MDA-MB-231 breast cancer cell line during long-term drug exposure. The complexes with small cycloalkylamine ligands (3–6) were inferior, those with large cycloalkylamine ligands were comparable (7) or superior (8) to cisplatin. Surprisingly, thecis/trans isomers7/9 and8/10 were equally active. All cycloalkylamine ligands were inactive. IR-spectroscopic studies showed that the size of the cycloalkylamine ring does not lead to significant differences in the Pt-Cl binding strength. Therefore it is assumed that the markedly stronger antitumor activity of the higher homologues,7–10, is not the result of a faster reaction with bionucleophils such as DNA. A possible explanation of the high activity of7–10 is the strong lipophilicity of the complexes. This assumption was confirmed by toxicity tests against confluent cultures.

Zusammenfassung

Die Synthese von Dichlorobis(cycloalkylamin)platin(II)-Komplexen mitcis- undtrans-ständigen Cycloalkylaminliganden [cis-PtCl2(C3H5NH2)2 biscis-PtCl2(C8H15NH2)2 (3–8) sowietrans-PtCl2(C7H13NH2)2 (9) undtrans-PtCl2(C8H15NH2)2 (10)] wird beschrieben. Eine Unterscheidung zwischencis- undtrans-Isomeren konnte mit Hilfe der1H-NMR-Spektroskopie getroffen werden. Die tumorwachstumshemmende Wirkung wurde im Langzeitversuch an der menschlichen MDA-MB-231 Brustkrebszellinie bestimmt. Die Komplexe mit kleinen Cycloalkylaminliganden (3–6) waren weniger, diejenigen mit großen Cycloalkylaminliganden vergleichbar (7) oder besser (8) wirksam als Cisplatin. Überraschenderweise waren diecis/trans Isomeren7/9 und8/10 gleich aktiv. Sämtliche Cycloalkylaminliganden waren unwirksam. IR-spektroskopische Untersuchungen zeigen, daß die Größe des Cycloalkylaminliganden zu keiner signifikanten Veränderung der Pt-Cl Bindungsstärke führt. Es wird angenommen, daß die deutlich stärkere Antitumoraktivität der höheren Homologen7–10 nicht auf eine schnellere Reaktion mit Bionucleophilen wie der DNA zurückzuführen ist. Eine mögliche Erklärung der hohen Aktivität von7–10 liegt in der starken Lipophilie der Komplexe. Diese Annahme wird durch Cytotoxizitätstests an stationären Kulturen gestützt.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Connors T. A., Jones M., Ross W. C. J., Braddock P. D., Khokhar A. R., Tobe M. L. (1972) Chem. Biol. Interactions5: 415

    Google Scholar 

  2. Braddock P. D., Connors T. A., Jones M., Khokhar A. R., Mack D. H., Tobe M. L. (1975) Chem. Biol. Interactions11: 145

    Google Scholar 

  3. Connors T. A., Cleare M. J., Harrap K. R. (1979) Cancer Treat. Rep.63(9–10): 1499

    Google Scholar 

  4. Bernhardt G., Reile H., Birnböck H., Spruß T., Schönenberger H. (1992) J. Cancer Res. Clin. Oncol.118: 35

    Google Scholar 

  5. Kritzenberger J., Zimmermann F., Wokaun A. Inorg. Chim. Acta (submitted)

  6. Kritzenberger J., Yersin H., Zabel M., Range K.-J. Inorg. Chim. Acta (submitted)

  7. Howard-Lock H. E., Lock C. J. L., Turner G., Zvagulis M. (1981) Can. J. Chem.59: 2737

    Google Scholar 

  8. Lippman M. E., Monaco M. E., Bolan G. (1977) Cancer Res.37: 1901

    Google Scholar 

  9. Reile H., Birnböck H., Bernhardt G., Spruß T., Schönenberger H. (1990) Anal. Biochem.187: 262

    Google Scholar 

  10. Hartley F. R. (1973) Chem. Soc. Rev.2(2): 163

    Google Scholar 

  11. Chatt J., Duncanson L. A., Venanzi L. M. (1955) Inorg. Subst. React. PartI: 4456

    Google Scholar 

  12. Burdett J. K. (1977) Inorg. Chem.16: 3013

    Google Scholar 

  13. Kauffman G. B., Cowan D. O. (1963) Inorg. Synth.7: 239

    Google Scholar 

  14. Hicks C. P., Spiro M. (1985) React. Kinet. Catal. Lett.29(1): 27

    Google Scholar 

  15. Lock C. J. L., Zvagulis M. (1981) Inorg. Chem.20: 1817

    Google Scholar 

  16. Zanotti G., Del Pra A., Bombieri G., Tamburro A. M. (1978) Acta Cryst.B34: 2138

    Google Scholar 

  17. Bradford J. P., Faggiani R., Lock C. J. L. (1981) Acta Cryst.B37: 243

    Google Scholar 

  18. Cherchi V., Faraglia G., Sindellari L., Voltarel G., Siotran S., Furlani A., Ravalico L., Scarcia V. (1988) Platinum and other Metal Coordination Compounds in Cancer Chemotherapy, Martinus Nijhoff, Boston, p. 643

    Google Scholar 

  19. Ha T. B. T., Souchard J.-P., Wimmer F. L., Johnson N. P. (1990) Polyhedron9: 2647

    Google Scholar 

  20. Bancroft D. P., Lepre C. A., Lippard S. J. (1990) J. Am. Chem. Soc.112: 6860

    Google Scholar 

  21. Butour J.-L., Alvinerie P., Souchard J.-P., Colson P., Houssier C., Johnson N. P. (1991) Eur. J. Biochem.202: 975

    Google Scholar 

  22. Souchard J.-P., Ha T. T. B., Cros S., Johnson N. P. (1991) J. Med. Chem.34: 863

    Google Scholar 

  23. Rosenberg B., Van Camp L., Trosko J. E., Mansour V. H. (1969) Nature222: 385

    Google Scholar 

  24. Farrell N., Ha T. T. B., Souchard J.-P., Wimmer F. L., Cros S., Johnson N. P. (1989) J. Med. Chem.32: 2240

    Google Scholar 

  25. Hollis L. S., Amundsen A. R., Stern E. W. (1989) J. Med. Chem.32: 128

    Google Scholar 

  26. Cleare M. J., Hoeschele J. D. (1973) Platinum Metals Rev.17(1): 2

    Google Scholar 

  27. Sherman S. E., Lippard S. J. (1987) Chem. Rev.87: 1153

    Google Scholar 

  28. Lippert B. (1988) Gaz. Chim. Ital.118: 153

    Google Scholar 

  29. Lepre C. A., Lippard S. J. (1990) In: Eckstein F., Lilley D. M. J. (eds) Nucleic Acids and Molecular Biology, vol. 4. Springer, Berlin Heidelberg New York Tokyo p. 9

    Google Scholar 

  30. Reedijk J. (1987) Pure & Appl. Chem.59(2): 181

    Google Scholar 

  31. Alazard R., Germanier M., Johnson N. P. (1982) Mutat. Res.93: 327

    Google Scholar 

  32. Plooy A. C. M., van Dijk M., Lohman P. H. M. (1984) Cancer Res.44: 2043

    Google Scholar 

  33. Ciccarelli R. B., Soloman M. J., Varshavsky A., Lippard S. J. (1985) Biochemistry24: 7533

    Google Scholar 

  34. Roberts J. J., Friedlos F. (1987) Cancer Res.47: 31

    Google Scholar 

  35. Pascoe J. M., Roberts J. J. (1974) Biochem. Pharmacol.23: 1345

    Google Scholar 

  36. Bernges F., Holler E. (1988) Biochemistry27: 6398

    Google Scholar 

  37. Bernges F., Holler E. (1990) Eur. J. Biochem.191: 743

    Google Scholar 

  38. Koch M., Bernhardt G. (1991) J. Cancer Res. Clin. Oncol.117 [Suppl.]: 104

    Google Scholar 

Download references

Author information

Author notes

  1. J. Kritzenberger

    Present address: Department of Chemistry, University of California, 94720, Berkeley, California, U.S.A.

Authors and Affiliations

  1. Institut für Physikalische und Theoretische Chemie, Universität Regensburg, D-W-8400, Regensburg, Federal Republic of Germany

    J. Kritzenberger & H. Yersin

  2. Institut für Pharmazie, Lehrstuhl Pharmazeutische Chemie II, Universität Regensburg, D-W-8400, Regensburg, Federal Republic of Germany

    G. Bernhardt, R. Gust, P. Pistor & H. Schönenberger

Authors
  1. J. Kritzenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Bernhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Gust
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Pistor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Schönenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Yersin
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

In memory of Professor Dr. Günter Gliemann, late director of the Institut für Physikalische und Theoretische Chemie, Universität Regensburg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kritzenberger, J., Bernhardt, G., Gust, R. et al. Dichlorobis(cycloalkylamine)platinum(II) complexes structure activity relationship on the human MDA-MB-231 breast cancer cell line. Monatsh Chem 124, 587–604 (1993). https://doi.org/10.1007/BF00819526

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00819526

Keywords

Search

Navigation