Skip to main content
SpringerLink
Log in

Insights into the structure–activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

The structure–activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid–base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Rosenberg B, Van Camp L, Krigas T (1965) Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 205:698–699

    Article  CAS  PubMed  Google Scholar 

  2. Deconti RC, Toftness BR, Lange RC, Creasey WA (1973) Clinical and pharmacological studies with cis-diamminedichloroplatinum(II). Cancer Res 33:1310–1315

    CAS  PubMed  Google Scholar 

  3. Higby DJ, Wallace HJ, Albert DJ, Holland JF (1974) Diaminodichloroplatinum: a phase I study showing responses in testicular and other tumors. Cancer 33:1219–1225

    Article  CAS  PubMed  Google Scholar 

  4. Higby DJ, Wallace HJ, Holland JF (1973) Cis-diamminedichloroplatinum (NSC-119875): a phase I study. Cancer Chemother Rep 57:459–463

    CAS  PubMed  Google Scholar 

  5. Rozencweig M, Von Hoff DD, Slavik M, Muggia FM (1977) Cis-diamminedichloroplatinum (II). A new anticancer drug. Ann Intern Med 86:803–812

    Article  CAS  PubMed  Google Scholar 

  6. Brayfield A (2007) Martindale: the complete drug reference. Pharmaceutical Press, London

    Google Scholar 

  7. Lippert B (1999) Cisplatin: chemistry and biochemistry of a leading anticancer drug. Wiley, Basel. doi:10.1002/9783906390420.ch10

    Book  Google Scholar 

  8. Kelland LR, Farrell NP (eds) (2000) Platinum-based drugs in cancer therapy. Humana Press Inc., Totowa

  9. Berger G, Gelbcke M, Cauët E et al (2013) Synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines: tools for the NMR study of platinum-based anticancer compounds. Tetrahedron Lett 54:545–548. doi:10.1016/j.tetlet.2012.11.079

    Article  CAS  Google Scholar 

  10. Berger G, Gasper R, Lamoral-theys D et al (2010) Fourier transform infrared (FTIR) spectroscopy to monitor the cellular impact of newly synthesized platinum derivatives. Int J Oncol 37:679–686. doi:10.3892/ijo

    Article  CAS  PubMed  Google Scholar 

  11. Dufrasne F, Gelbcke M, Schnurr B, Gust R (2002) Synthesis and antitumor activity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)propane]dichloroplatinum(II) complexes. Arch Pharm (Weinheim) 335:229–239. doi:10.1002/1521-4184(200205)335:5<229:AID-ARDP229>3.0.CO;2-Q

    Article  CAS  Google Scholar 

  12. Dullin A, Dufrasne F, Gelbcke M, Gust R (2004) Enantiomerically pure [1, 2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LnCaP/FGC prostate cancer cell lines. Arch Pharm (Weinheim) 337:654–667. doi:10.1002/ardp.200400621

    Article  CAS  Google Scholar 

  13. Dullin A, Dufrasne F, Gelbcke M, Gust R (2006) Synthesis and cytotoxicity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes. ChemMedChem 1:644–653. doi:10.1002/cmdc.200600032

    Article  CAS  PubMed  Google Scholar 

  14. Berger G, Leclercqz H, Derenne A et al (2014) Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: a fast method for new compound discovery. Bioorg Med Chem 22:3527–3536. doi:10.1016/j.bmc.2014.04.017

    Article  CAS  PubMed  Google Scholar 

  15. Brouwer J, van de Putte P, Fichtinger-Schepmant AMJ, Reedijk J (1981) Base-pair substitution hotspots in GAG and GCG nucleotide sequences in Escherichia coli K-12 induced by cis-diamminedichloroplatinum (II). Proc Natl Acad Sci 78:7010–7014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Welters MJP, Fichtinger-schepman AMJ, Baan RA et al (1999) Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo. Br J Cancer 79:82–88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev 99:2467–2498

    Article  CAS  PubMed  Google Scholar 

  18. Bischin C, Lupan A, Taciuc V, Silaghi-dumitrescu R (2011) Interactions between proteins and platinum-containing anti-cancer drugs. Mini Rev Med Chem 11:214–224

    Article  CAS  PubMed  Google Scholar 

  19. Casini A, Reedijk J (2012) Interactions of anticancer Pt compounds with proteins: an overlooked topic in medicinal inorganic chemistry? Chem Sci 3:3135. doi:10.1039/c2sc20627g

    Article  CAS  Google Scholar 

  20. Karasawa T, Sibrian-Vazquez M, Strongin RM, Steyger PS (2013) Identification of cisplatin-binding proteins using agarose conjugates of platinum compounds. PLoS One. doi:10.1371/journal.pone.0066220

    PubMed Central  PubMed  Google Scholar 

  21. Pinato O, Musetti C, Sissi C (2014) Pt-based drugs: the spotlight will be on proteins. Metallomics 6:380–395. doi:10.1039/c3mt00357d

    Article  CAS  PubMed  Google Scholar 

  22. Mezencev R (2015) Interactions of cisplatin with non-DNA targets and their influence on anticancer activity and drug toxicity: the complex world of the platinum complex. Curr Cancer Drug Targets 14:794–816

    Article  PubMed  Google Scholar 

  23. Davis JT (2004) G-Quartets 40 years later: from 5′-GMP to molecular biology and supramolecular chemistry. Angew Chem Int Ed Engl 43:668–698. doi:10.1002/anie.200300589

    Article  CAS  PubMed  Google Scholar 

  24. Watson JD, Crick FHC (1953) Molecular structure of nucleic acids. Nature 171:737–738

    Article  CAS  PubMed  Google Scholar 

  25. Mergny J-L, Riou J-F, Mailliet P et al (2002) Natural and pharmacological regulation of telomerase. Nucleic Acids Res 30:839–865

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015

    Article  CAS  PubMed  Google Scholar 

  27. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  28. Parkinson GN, Lee MPH, Neidle S (2002) Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417:876–880. doi:10.1038/nature755

    Article  CAS  PubMed  Google Scholar 

  29. Wang Y, Patel DJ (1993) Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure 1:263–282

    Article  CAS  PubMed  Google Scholar 

  30. Granotier C, Pennarun G, Riou L et al (2005) Preferential binding of a G-quadruplex ligand to human chromosome ends. Nucleic Acids Res 33:4182–4190. doi:10.1093/nar/gki722

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Biffi G, Tannahill D, McCafferty J, Balasubramanian S (2013) Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem 5:182–186. doi:10.1038/nchem.1548

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Schaffitzel C, Berger I, Postberg J et al (2001) In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei. Proc Natl Acad Sci 98:8572–8577. doi:10.1073/pnas.141229498

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Gellert M, Lipsett MN, Davies DR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci 48:2013–2018

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Burger AM, Double JA, Newell DR (1997) Inhibition of telomerase activity by cisplatin in human testicular cancer cells. Eur J Cancer 33:638–644. doi:10.1016/S0959-8049(96)00521-7

    Article  CAS  PubMed  Google Scholar 

  35. Ourliac-garnier I, Charif R, Bombard S (2009) Telomeres and telomerase: potential targets for platinum complexes. In: Hadjiliadis N, Sletten E (eds) Metal Complex-DNA Interactions. Wiley, pp 209–235

  36. Schwartz A, Sip M, Leng M (1990) Sodium cyanide: a chemical probe of the conformation of DNA modified by the antitumor drug cis-diamminedichloroplatinum(II). J Am Chem Soc 112:3673–3674. doi:10.1021/ja00165a070

    Article  CAS  Google Scholar 

  37. Maxam AM, Gilbert W (1977) A new method for sequencing DNA. Proc Natl Acad Sci 74:560–564. doi:10.1073/pnas.74.2.560

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Ourliac-Garnier I, Elizondo-Riojas M-A, Redon S et al (2005) Cross-links of quadruplex structures from human telomeric DNA by dinuclear platinum complexes show the flexibility of both structures. Biochemistry 44:10620–10634. doi:10.1021/bi050144w

    Article  CAS  PubMed  Google Scholar 

  39. Bertrand H, Bombard S, Monchaud D, Teulade-Fichou M-P (2007) A platinum-quinacridine hybrid as a G-quadruplex ligand. J Biol Inorg Chem 12:1003–1014. doi:10.1007/s00775-007-0273-3

    Article  CAS  PubMed  Google Scholar 

  40. Davies MS, Cox JW, Berners-Price SJ et al (2000) Equilibrium and kinetic studies of the aquation of the dinuclear platinum complex [[trans-PtCl(NH3)2]2(mu-NH2(CH2)6NH2)]2+: pKa determinations of aqua ligands via [1H,15N] NMR spectroscopy. Inorg Chem 39:1710–1715

    Article  CAS  PubMed  Google Scholar 

  41. Cubo L, Thomas DS, Zhang J et al (2009) [1H,15N] NMR studies of the aquation of cis-diamine platinum(II) complexes. Inorg Chim Acta 362:1022–1026. doi:10.1016/j.ica.2008.03.117

    Article  CAS  Google Scholar 

  42. Chai J-D, Head-Gordon M (2008) Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections. Phys Chem Chem Phys 10:6615–6620. doi:10.1039/b810189b

    Article  CAS  PubMed  Google Scholar 

  43. Dolg M, Cao X (2012) Relativistic pseudopotentials: their development and scope of applications. Chem Rev 112:403–480. doi:10.1021/cr2001383

    Article  CAS  PubMed  Google Scholar 

  44. Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3093. doi:10.1021/cr9904009

    Article  CAS  PubMed  Google Scholar 

  45. Reed AE, Weinstock RB, Weinhold F (1985) Natural population analysis. J Chem Phys 83:735–746

    Article  CAS  Google Scholar 

  46. Szlachetko J, Nachtegaal M, de Boni E et al (2012) A von Hamos X-ray spectrometer based on a segmented-type diffraction crystal for single-shot X-ray emission spectroscopy and time-resolved resonant inelastic x-ray scattering studies. Rev Sci Instrum 83:103105

    Article  CAS  PubMed  Google Scholar 

  47. Redon S, Bombard S, Elizondo-Riojas M-A, Chottard JC (2003) Platinum cross-linking of adenines and guanines on the quadruplex structures of the AG3(T2AG3)3 and (T2AG3)4 human telomere sequences in Na+ and K+ solutions. Nucleic Acids Res 31:1605–1613. doi:10.1093/nar/gkg259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Howe-Grant M, Lippard SJ (1980) Metallointercalation reagents: thiolato complexes of (2, 2′: 6′, 2′′-terpyridine)-platinum(II). Inorg Synth 20:101–105

    Google Scholar 

  49. Berners-Price SJ, Ronconi L, Sadler PJ (2006) Insights into the mechanism of action of platinum anticancer drugs from multinuclear NMR spectroscopy. Prog Nucl Magn Reson Spectrosc 49:65–98. doi:10.1016/j.pnmrs.2006.05.002

    Article  CAS  Google Scholar 

  50. Appleton TG, Hall JR, Ralph SF, Thompson CSM (1989) NMR of acid-base equilibria and other reactions of ammineplatinum complexes with aqua and hydroxo ligands. Inorg Chem 28:1989–1993

    Article  Google Scholar 

  51. Berners-Price SJ, Frenkiel TA, Frey U et al (1992) Hydrolysis products of cisplatin: pKa determinations via[1H, 15N] NMR spectroscopy. J Chem Soc, Chem Commun. doi:10.1039/C39920000789

    Google Scholar 

  52. Pearson RG (1963) Hard and soft acids and bases. J Am Chem Soc 85:3533–3539. doi:10.1021/ja00905a001

    Article  CAS  Google Scholar 

  53. Parr RG, Yang W (1984) Density functional approach to the frontier-electron theory of chemical reactivity. J Am Chem Soc 106:4049–4050. doi:10.1021/ja00326a036

    Article  CAS  Google Scholar 

  54. Parr RG, Szentpaly LV, Liu S (1999) Electrophilicity index. J Am Chem Soc 121:1922–1924. doi:10.1021/cr040109f

    Article  CAS  Google Scholar 

  55. Chattaraj PK, Sarkar U, Roy DR (2006) Electrophilicity index. Chem Rev 106:2065–2091. doi:10.1021/cr040109f

    Article  CAS  PubMed  Google Scholar 

  56. Geerlings P, De Proft F, Langenaeker W (2003) Conceptual density functional theory. Chem Rev 103:1793–1873. doi:10.1021/cr990029p

    Article  CAS  PubMed  Google Scholar 

  57. Yang W, Mortier WJ (1986) The use of global and local molecular parameters for the analysis of the gas-phase basicity of amines. J Am Chem Soc 108:5708–5711. doi:10.1021/ja00279a008

    Article  CAS  PubMed  Google Scholar 

  58. Koopmans T (1934) Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den Einzelnen Elektronen Eines Atoms. Physica 1:104–113. doi:10.1016/S0031-8914(34)90011-2

    Article  Google Scholar 

  59. Gust R, Gelbcke M, Angemaier B et al (1997) The stereoselectivity of antitumor active [1,2-diamino-1-phenylpropane] dichloroplatinum(II) complexes. Inorg Chim Acta 264:145–160

    Article  CAS  Google Scholar 

  60. Simon M, Schmitt T (eds) (2013) Progress in resonant inelastic X-ray scattering. Elsevier, Amsterdam, pp 1–182

  61. Sa J, Szlachetko J, Kleymenov E et al (2013) Fine tuning of gold electronic structure by IRMOF post-synthetic modification. RSC Adv 3:12043–12048. doi:10.1039/C3RA40970H

    Article  CAS  Google Scholar 

  62. Szlachetko J, Sá J, Nachtegaal M et al (2014) Real time determination of the electronic structure of unstable reaction intermediates during Au2O3 reduction. J Phys Chem Lett 5:80–84. doi:10.1021/jz402309s

    Article  CAS  Google Scholar 

  63. Sa J, Kayser Y, Milne CJ et al (2014) Temperature-programmed reduction of NiO nanoparticles followed by time-resolved RIXS. Phys Chem Chem Phys 16:7692–7696. doi:10.1039/C3CP54622E

    Article  CAS  PubMed  Google Scholar 

  64. Hammer B, Norskov JK (1995) Why gold is the noblest of all the metals. Nature 376:238–240

    Article  CAS  Google Scholar 

  65. Bligaard T, Nørskov JK, Dahl S et al (2004) The Brønsted-Evans-Polanyi relation and the volcano curve in heterogeneous catalysis. J Catal 224:206–217. doi:10.1016/j.jcat.2004.02.034

    Article  CAS  Google Scholar 

  66. Ankudinov AL, Rehr JJ, Conradson SD (1998) Real-space multiple-scattering calculation and interpretation of X-ray-absorption near-edge structure. Phys Rev B 58:7565–7576. doi:10.1103/PhysRevB.58.7565

    Article  CAS  Google Scholar 

  67. Rehr JJ, Albers RC (2000) Theoretical approaches to X-ray absorption fine structure. Rev Mod Phys 72:621–654. doi:10.1103/RevModPhys.72.621

    Article  CAS  Google Scholar 

  68. Ankudinov AL, Rehr JJ, Low J, Bare SR (2001) Effect of hydrogen adsorption on the X-ray absorption spectra of small Pt clusters. Phys Rev Lett 86:1642–1645. doi:10.1103/PhysRevLett.86.1642

    Article  CAS  PubMed  Google Scholar 

  69. Summa N, Schiessl W, Puchta R et al (2006) Thermodynamic and kinetic studies on reactions of Pt(II) complexes with biologically relevant nucleophiles. Inorg Chem 45:2948–2959. doi:10.1021/ic051955r

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Elisa Torres for the pKa measurements completed in the framework of her graduation thesis.

Author information

Authors and Affiliations

  1. Laboratoire de Chimie Pharmaceutique Organique, Université Libre de Bruxelles, Campus Plaine CP205/5, Bd du Triomphe, 1050, Brussels, Belgium

    Gilles Berger & François Dufrasne

  2. Laboratoire de Résonance Magnétique Nucléaire Haute Résolution, Université Libre de Bruxelles (ULB), Avenue F.D. Roosevelt 50, CP160/08, 1050, Brussels, Belgium

    Luca Fusaro & Michel Luhmer

  3. The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland

    Joanna Czapla-Masztafiak & Ewelina Lipiec

  4. Paul Scherrer Institute (PSI), Villigen, Switzerland

    Jakub Szlachetko & Yves Kayser

  5. Institute of Physics, Jan Kochanowski University in Kielce, Kielce, Poland

    Jakub Szlachetko

  6. Ångström Laboratory, Department of Chemistry, Uppsala University, Uppsala, Sweden

    Daniel L. A. Fernandes & Jacinto Sá

  7. Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland

    Jacinto Sá

  8. Homéostasie Cellulaire et Cancer, UMR-S INSERM 1007, Université Paris Descartes, 45 rue des Saint-Pères, 75006, Paris, France

    Sophie Bombard

Authors
  1. Gilles Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Fusaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michel Luhmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joanna Czapla-Masztafiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ewelina Lipiec
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jakub Szlachetko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yves Kayser
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel L. A. Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jacinto Sá
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. François Dufrasne
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sophie Bombard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gilles Berger.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2013 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Berger, G., Fusaro, L., Luhmer, M. et al. Insights into the structure–activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives. J Biol Inorg Chem 20, 841–853 (2015). https://doi.org/10.1007/s00775-015-1270-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-015-1270-6

Keywords

Search

Navigation