Platinum-Based Organometallic Complexes of Vitamin C and Related Analogs as Antitumor Agents

  • S. L. Hollis
  • S. L. Doran
  • A. R. Amundsen
  • E. W. Stern
Part of the Developments in Oncology book series (DION, volume 54)

Abstract

While cisplatin has proven effective as a antitumor agent in treating a variety of forms of cancer, such as testicular and ovarian carcinomas,1 a substantial effort has been made in new drug development programs to improve the therapeutic properties of platinum-based antitumor agents.2 Major objectives of research in this area include the development of new agents that have an improved spectrum of activity and are more effective and less toxic than cisplatin.3 To date these efforts have produced a number of new compounds that show good activity in various animal tumor screens.4 While recent clinical studies show that some second-generation analogs, such as carboplatin, cis-[Pt(NH3)2-(1,1 -cyclobutanedicarboxylate)]5, are less toxic than cisplatin, the search for new agents that display a significantly different spectrum of activity is continuing in laboratories worldwide.

Keywords

DMSO Platinum Titration Recrystallization Carbonyl 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Loehrer, P.J.; Einhorn, L.H. Ann. Intern Med. 1984,100,704.PubMedGoogle Scholar
  2. 2(a).
    Hacker, M.P.; Douple, E.B.; Krakoff, I.H., Eds.; “Platinum Coordination Complexes in Cancer Chemotherapy”; Martinus-Nijhoff: Boston, 1984.Google Scholar
  3. 2(b).
    Prestayko, A.E.; Crooke, S.T.; Carter, S.K., Eds.; “Cis-platin, Status and New Developments”; Academic Press: New York, 1980.Google Scholar
  4. 2(c).
    Lippard, S.J., Ed.; “Platinum, Gold and Other Metal Chemo-therapeutic Agents”; American Chemical Society: Washington, D.C., 1983; ACS Symp. Ser. No. 209.Google Scholar
  5. 2(d).
    McBrien, D.C.H.; Slater, T.F., Eds.; “Biochemical Mechanism of Platinum Antitumor Drugs”; IRL Press, Washington, DC, 1986.Google Scholar
  6. 3.
    Carter, S.K. In ref 2a, p 359.Google Scholar
  7. 4.
    Rose, W.C.; Bradner, W.T. In ref 2b, p. 229.Google Scholar
  8. 5(a).
    Egorin, M.J.; Van Echo, D.A.; Olman, E.A.; Whitacre, M.Y.; Forrest, A.; Aisner, J. Cancer Res. 1985,45,6502.Google Scholar
  9. 5(b).
    Calvert, A.H. In ref 2d, p 307.Google Scholar
  10. 5(c).
    Barnard, C.F.J.; Cleare, M.J.; Hydes, P.C. Chem. Brit. 1986, 22,1001.Google Scholar
  11. 6.
    Appleton, T.G.; Hall, J.R.; Ralph, S.F. Inorg. Chem. 1985, 24,4685.CrossRefGoogle Scholar
  12. 7.
    Hollis, L.S.; Stern, E.W.; Amundsen, A.R.; Miller, A.V.; Doran, S.L. J. Am. Chem. Soc. 1987,109,3596.CrossRefGoogle Scholar
  13. 8.
    Hollis, L.S.; Amundsen, A.R.; Stern, E.W. J. Am. Chem. Soc. 1985,107,274.CrossRefGoogle Scholar
  14. 9.
    Crystallographic data. [Pt(S,S-dach) (C2,O5-Asc)] 5H2O crystallizes in the orthorhombic space group P212121 with the following cell parameters: a = 12.366(1), b = 22.371(3), c = 6.782(1) Å, V = 1876.3 Å3, Z = 4. The structure was solved by using standard Patterson and Fourier methods using 1943 reflections (2θ < 50°) collected on an Enraf-Nonius CAD-4F diffractometer. Refinement of the absorption corrected data, with all atoms (execpt H) assigned anisotropic thermal parameters converged at Rf = 0.033 and Rw = 0.045. Full details will be reported at a later date.Google Scholar
  15. 10.
    Basch, H.; Krauss, M.; Stevens, W.J.; Inorg. Chem. 1986,25, 4777.CrossRefGoogle Scholar
  16. 11.
    Hollis, L.S.; Stern, E.W. Inorg. Chem. Submitted for publication.Google Scholar
  17. 12.
    Farrel, N. In ref 2c, p 279.CrossRefGoogle Scholar
  18. 13.
    Crystallographic data. [Pt(R,R-dach)(C2-CHD)(O1-CHD)] (16) crystallizes in the space group PI with the following cell parameters: a = 10.225(1), b = 11.841(1), c = 9.387(1) Å, α = 112.15(1)°, β = 106.15(1)°, γ = 87.91(1)°, V = 1008.2 Å3, Z = 2. The structure was solved by using standard Patterson and Fourier methods using 4475 unique reflections (20 < 54°). Refinement of the absorption corrected data, with all atoms, except Pt, N and O, assigned isotropic thermal parameters converged at Rf = 0.023 and Rw = 0.025. Full details will be reported at a later date.Google Scholar
  19. 14.
    Crystallographic data. [Pt(en)(C3,O8-CPD2)] (19) crystallizes in the triclinic space group P1 with the following cell parameters: a = 10.528(2), b = 11.533(2), c = 7.728(1) Å,α= 89.91(1)°, β= 106.25(1)°, γ = 70.92(1)°, V = 841.0 Å3, Z = 2. The structure was solved as in ref 9, using 2098 reflections (2θ < 45°). Refinement of the absorption corrected data, with all atoms (except H) assigned anisotropic thermal parameters converged at Rf = 0.019 and Rw = 0.029. Full details will be reported at a later date.Google Scholar
  20. 15.
    The test protocol for the S180a screen is described in ref 16. Compounds were administered on day one using 6 mice/dose; an ILS > 50% indicates activity. The reported dose is that which gave the the best %ILS. The test protocol for the L1210 screen is given in ref 17. Compounds were administered on day one and an ILS > 25% indicates activity. Surviving mice were counted as dying on the day of evaluation.Google Scholar
  21. 16.
    Amundsen, A.R.; Stern, E.W. U.S. Patent 4 457 926, 1984.Google Scholar
  22. 17.
    Rose, W.C.; Schurig, J.E.; Huftalen, J.B.; Bradner, W.T. Cancer Treat. Rep. 1982,66,135.PubMedGoogle Scholar
  23. 18.
    Data not shown.Google Scholar
  24. 19.
    Abbreviations: CHD, 1,3-cyclohexanedione; MCHD, 5-methyl-CHD; DCHD, 5,5-dimethyl-CHD; CPD, 1,3-cyclopentanedione; CPD2, CPD dimer.Google Scholar
  25. 20(a).
    Kidani, Y.; Inagaki, K.; Iigo, M.; Hoshi, A.; Kuretani, K. J. Med. Chem. 1978,21,1315.PubMedCrossRefGoogle Scholar
  26. 20(b).
    Kidiani, Y.; Inagaki, K.; Saito, R.; Tsukagoshi, S. Wadley Med. Bull. 1977,7,197.Google Scholar
  27. 20(c).
    Saito, R.; Kidani, Y. Bull. Chem. Soc. Jpn. 1986,59,1689.CrossRefGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1988

Authors and Affiliations

  • S. L. Hollis
  • S. L. Doran
  • A. R. Amundsen
  • E. W. Stern

There are no affiliations available

Personalised recommendations