Advertisement

Factors Affecting Formation and Structure of DNA Intrastrand Cross-Links by Dinuclear Platinum Complexes

  • Y. Qu
  • M. J. Bloemink
  • K. J. Mellish
  • H. Rauter
  • K. A. Smeds
  • N. Farrell
Chapter
  • 251 Downloads
Part of the NATO ASI Series book series (ASEN2, volume 26)

Abstract

Dinuclear platinum complexes are currently undergoing pre-clinical evaluation. The development of this series has been driven by the hypothesis that a different spectrum of antitumor activity in comparison to that of cisplatin (cis-[PtCl2(NH3)2], cis-DDP) will be achieved by altering the mode of DNA binding relative to that of cisplatin and its analogues. Dinuclear platinum complexes form a unique array of DNA adducts including (Pt, Pt) interstrand and (Pt, Pt) intrastrand cross-links. A (Pt, Pt) intrastrand adduct between two adjacent guanines is the structural analog of the major adduct formed by cis-DDP2. This cis-DDP-d(GpG) adduct produces a rigid, directed bend 30-35° into the major groove of DNA, confirmed by both X- ray and NMR structural determinations on oligonucleotide fragments containing site-specific adducts3, 4. This bend is recognised by damage recognition proteins containing the HMG-binding domain5. In contrast, the global structural distortions of DNA induced by the dinuclear platinum complexes are recognized only weakly by HMG-domain proteins.6 This contribution summarises our results on the structural reasons for these differences, as exemplified by comparative studies on DNA-DNA intrastrand adducts between adjacent guanines.

Keywords

Platinum Complex Major Groove Steric Hinderance Dinuclear Platinum Adjacent Guanine 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Farrell, N. (1995) DNA Binding and Chemistry of Dinuclear Platinum Complexes, Comments in Inorganic Chemistry, 16, 373–389.CrossRefGoogle Scholar
  2. 7.
    Bloemink, M.J. and Reedijk, J. (1996) Cisplatin and Derived Anticancer Drugs: Mechanism and Current Status of DNA Binding. Metal Ions in Biological Systems, 32, 641–685.Google Scholar
  3. 3.
    Takahara, P.M.; Rosenzweig, A.C.; Frederick, C.A. and Lippard, S.J. (1995) Crystal Structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin, Nature, 377, 649–657.CrossRefGoogle Scholar
  4. 4.
    Yang, D.; van Boom. S.S.G.E.; Reedijk, J.; van Boom. J.H. and Wang, A.H.-J. (1995) Structure and Isomerization of an Interstrand Cisplatin-Cross-Linked Octamer DNA Duplex by NMR Analysis. Biochemistry, 34, 12917–12920.Google Scholar
  5. 5.
    Whitehead, J.P. and Lippard, S.J. (1996) Proteins that Bind to and Mediate the Biological Activity of Platinum Anticancer Drug-DNA Adducts, Metal Ions in Biological Systems, 32, 687–776.Google Scholar
  6. 6.
    Farrell, N., Appleton, T.G., Qu, Y., Roberts, J.D., Soares Fontes, A.P., Skov, K.A., Wu, P. and Zou, Y. (1995) Effects of Geometric Isomerism and Ligand Substitution in Bifunctional Dinuclear Platinum Complexes on Binding Properties and Conformational Changes in DNA, Biochemistry, 34, 15480–15486.CrossRefGoogle Scholar
  7. 7.
    Kasparkova, J., Mellish, K.J., Qu, Y., Brabec, V. and Farrell, N. Site-Specific d(GpG) Intrastrand Cross-links Formed By Dinuclear Platinum Complexes, Bending and NMR Studies, Biochemistry, In Press.Google Scholar
  8. 8.
    Qu, Y., Bloemink, M.J., Reedijk, J., Hambley, T.W., and Farrell, N. (1996) Dinuclear Platinum Complexes Form a Novel Intrastrand Adduct with d(GpG)-an anti-syn conformation of the macrochelate as observed by MR and molecular modeling. J. Am. Chem. Soc. 118, 9307–9313.CrossRefGoogle Scholar
  9. 9.
    Spellmeyer Fouls, C., Marzilli, L.G., Byrd, R.A., Summers, M.F., Zon, G. and Shinozuka, K. (1988) HMQC and 1H and 31 P NMR Studies of Platinum Amine Adducts of Tetradeoxyribonucleotides. Relationship Between 31P Shift and Potential Hydrogen-Bonding Interactions in pGpG Moieties Cross-linked byPlatinum, Iuorg Chem. 27, 366–376.CrossRefGoogle Scholar
  10. 10.
    Mellish, K.J., Qu, Y. and Farrell, N. Effect of Geometric Inomerism in Dinuclar Platinum Antitumor Complexes on the Rate of Formation and Structure of Intrastrand Adducts with Oligonucleotides, Nuc. Acids Res., Submitted.Google Scholar
  11. 11.
    Qu, Y. and Farrell, N. (1991) Interaction of Bis(platinum) Complexes with the Mononucleotide 5′-Guanosine Monophosphate (5′-GMP). ERffect of Diamine Linker and the Nature of the Bis(platinum) Complex on Product Formation, J. Am. Chem. Soc., 113, 4851–4856.CrossRefGoogle Scholar
  12. 12.
    Van Houten, B., Illenye, S., Qu, Y. and Farrell, N. (1993) Homodinuclear (Pt, Pt) and Heterodinuclear (Ru, Pt) Metal Complexes as DNA-Protein Cross-linking Agents: Potential Suicide DNA Lesions. Biochemistry 32, 11794–11801.CrossRefGoogle Scholar
  13. 13.
    Farrell, N. (1993) Non-classical Platinum Antitumor Complexes. Perspectives for Design and Development of New Drugs Complementary to Cisplatin, Cancer Investigation, 11, 578–589.CrossRefGoogle Scholar
  14. 14.
    Yohannes, P.G.; Zon, G.; Doetsch, P.W. and Marzilli, L.G. (1993) DNA Hairpin Formation in Adducts with Platinum Anticancer Drugs: Gel Electrophoresis Provides New Information and a Caveat, J. Am. Chem. Soc., 115, 5105–5110.CrossRefGoogle Scholar
  15. 15.
    Huaug, H.; Zhu, L.; Reid, B.R.; Drobny, G.P. and Hopkins, P.B. (1995) Solution Structure of a Cisplatin-Induced DNA Interstrand Cross-link, Science, 270, 1842–1845.CrossRefGoogle Scholar
  16. 16.
    Yang, D., Van Boom, S.S.G.E., Reedijk, J., Van Boom, J.H., Farrell, N. and Wang, A.H.-J. (1995) A novel DNA structure induced by the new dinuclear anticancer compound μ-(1, 4-diamiuobutane)-bis[traus-diamminechloroplatinum(II)] crosslinked to a GpG site in DNA, Nat Struct Biol., 2, 577–586.CrossRefGoogle Scholar
  17. 17.
    Kharatishvili, M.; Qu, Y. and Farrell, N. Z-DNA Formation by Dinuclear Platinum Complexes is Irreversible, Nuc. Acids Res., Submitted.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1997

Authors and Affiliations

  • Y. Qu
    • 1
  • M. J. Bloemink
    • 1
  • K. J. Mellish
    • 1
  • H. Rauter
    • 1
  • K. A. Smeds
    • 1
  • N. Farrell
    • 1
  1. 1.Department of ChemistryVirginia Commonwealth UniversityRichmondUSA

Personalised recommendations