Skip to main content
SpringerLink
Log in

X-ray absorption spectroscopy studies of the adducts formed between cytotoxic gold compounds and two major serum proteins

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

Abstract

Gold metallodrugs form a class of promising antiproliferative agents showing a high propensity to react with proteins. We exploit here X-ray absorption spectroscopy (XAS) methods [both X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS)] to gain insight into the nature of the adducts formed between three representative gold(I, III) metallodrugs (i.e., auranofin, [Au(2,2′-bipyridine)(OH)2](PF6), Aubipy, and dinuclear [Au2(6,6′-dimethyl-2,2′-bipyridine)2(μ-O)2](PF6)2, Auoxo6) and two major plasma proteins, namely, bovine serum albumin (BSA) and human serum apotransferrin (apoTf). The following metallodrug–protein systems were investigated in depth: auranofin/apoTf, Aubipy/BSA, and Auoxo6/apoTf. XANES spectra revealed that auranofin, upon protein binding, conserves its gold(I) oxidation state. Protein binding most probably takes place through release of the thiosugar ligand and its subsequent replacement by a thiol (or a thioether) from the protein. This hypothesis is independently supported by EXAFS results. In contrast, the reactions of Aubipy with serum albumin and of Auoxo6 with serum apoTf invariantly result in gold(III) to gold(I) reduction. Gold(III) reduction, clearly documented by XANES, is accompanied, in both cases, by release of the bipyridyl ligands; for Auoxo6 cleavage of the gold–gold dioxo bridge is also observed. Gold(III) reduction leads to formation of protein-bound gold(I) species, with deeply modified metal coordination environments, as evidenced by EXAFS. In these adducts, the gold(I) centers are probably anchored to the protein through nitrogen donors. In general, these two XAS methods, i.e., XANES and EXAFS, used here jointly, allowed us to gain independent structural information on metallodrug/protein systems; detailed insight into the gold oxidation state and the local environment of protein-bound metal atoms was achieved in the various cases.

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

Similar content being viewed by others

References

  1. http://www.cost.esf.org/

  2. Espósito BP, Najjar R (2002) Coord Chem Rev 232:137

    Article  Google Scholar 

  3. Liang X, Campopiano DJ, Sadler PJ (2007) Chem Soc Rev 36:968

    Article  PubMed  CAS  Google Scholar 

  4. Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224

    Article  PubMed  CAS  Google Scholar 

  5. Christodoulou J, Sadler PJ, Tucker A (1995) FEBS Lett 376:1

    Article  PubMed  CAS  Google Scholar 

  6. Patel SU, Sadler PJ, Tucker A, Viles JH (1993) J Am Chem Soc 115:9285

    Article  CAS  Google Scholar 

  7. Nobili S, Mini E, Landini I, Gabbiani C, Casini A, Messori L (2010) Med Res Rev 30:550

    PubMed  CAS  Google Scholar 

  8. Casini A, Kelter G, Gabbiani C, Cinellu MA, Minghetti G, Fregona D, Fiebig HH, Messori L (2009) J Biol Inorg Chem 14:1139

    Article  PubMed  CAS  Google Scholar 

  9. Ivanov AI, Christodoulou J, Parkinson JA, Barnham KJ, Tucker A, Woodrow J, Sadler PJ (1998) J Biol Chem 273:14721

    Article  PubMed  CAS  Google Scholar 

  10. Shaw CF III (1999) Chem Rev 99:2589

    Article  CAS  Google Scholar 

  11. Marcon G, Messori L, Orioli P, Cinellu MA, Minghetti G (2003) Eur J Biochem 270:4655

    Article  PubMed  CAS  Google Scholar 

  12. Talib J, Beck JL, Ralph SF (2006) J Biol Inorg Chem 11:559

    Article  PubMed  CAS  Google Scholar 

  13. Boffi F, Ascone I, Della Longa S, Girasole M, Yalovega G, Soldatov A, Varoli-Piazza A, Congiu Castellano A (2003) Eur Biophys J 32:329

    Article  PubMed  CAS  Google Scholar 

  14. Ascone I, Strange R (2009) J Synchrotron Radiat 16:413

    Article  PubMed  CAS  Google Scholar 

  15. Michalke BJ (2010) Trace Elem Med Biol 24:69

    Article  CAS  Google Scholar 

  16. Gabbiani C, Magherini F, Modesti A, Messori L (2010) AntiCancer Agents Med Chem 10:324

    PubMed  CAS  Google Scholar 

  17. Levina A, Mitra A, Lay PA (2009) Metallomics 1:458

    Article  PubMed  CAS  Google Scholar 

  18. Finney L, Chishti Y, Khare T, Giometti C, Levina A, Lay PA, Vogt S (2010) ACS Chem Biol 5:577

    Article  PubMed  CAS  Google Scholar 

  19. Lobinski R, Moulin C, Ortega R (2006) Biochimie 88:1591

    Article  PubMed  CAS  Google Scholar 

  20. Ortega R, Devès G, Carmona A (2009) J R Soc Interface 5:S649

    Article  Google Scholar 

  21. Ascone I, Messori L, Casini A, Gabbiani C, Balerna A, Dell’Unto F, Congiu Castellano A (2008) Inorg Chem 47:8629

    Article  PubMed  CAS  Google Scholar 

  22. Liu M, Lim ZJ, Gwee YY, Levina A, Lay PA (2010) Angew Chem Int Ed 49:1661

    CAS  Google Scholar 

  23. Hall MD, Foran GJ, Zhang M, Beale PJ, Hambley TW (2003) J Am Chem Soc 125:7524

    Article  PubMed  CAS  Google Scholar 

  24. Hall MD, Alderden RA, Zhang M, Beale PJ, Cai Z, Lai B, Stampfl APJ, Hambley TW (2006) J Struct Biol 155:38

    Article  PubMed  CAS  Google Scholar 

  25. Laib JE, Shaw CF 3rd, Petering DH, Eidsness MK, Elder RC, Garvey JS (1985) Biochemistry 24:1977

    Article  PubMed  CAS  Google Scholar 

  26. Coffer MT, Shaw CF III, Eidsness MK, Watkins JW II, Elder RC (1986) Inorg Chem 25:333

    Article  Google Scholar 

  27. Elder RC, Eidsness MK (1987) Chem Rev 87:1027

    Article  CAS  Google Scholar 

  28. Soldatov MA, Ascone I, Congiu-Castellano A, Messori L, Cinellu MA, Balerna A, Soldatov AV, Yalovega G (2009) J Phys Conf Ser 190:012210

    Google Scholar 

  29. Casini A, Cinellu MA, Minghetti G, Gabbiani C, Coronnello M, Mini E, Messori L (2006) J Med Chem 49:5524

    Article  PubMed  CAS  Google Scholar 

  30. Ciatto G, D’Acapito F, Boscherini F, Mobilio S (2004) J Synchrotron Radiat 11:278

    Article  PubMed  CAS  Google Scholar 

  31. Pascarelli S, D’Acapito F, Antonioli G, Balerna A, Boscherini F, Cimino R, Dalba G, Fornasini P, Licheri G, Meneghini C, Rocca F, Mobilio S (1995) ESRF Newsl 23:17

    Google Scholar 

  32. Lee PA, Citrin PH, Eisenberger P, Kincaid BM (1981) Rev Mod Phys 53:769

    Article  CAS  Google Scholar 

  33. Hill DT, Sutton BM (1980) Cryst Struct Commun 9:679

    CAS  Google Scholar 

  34. Tong YY, Pombiero AJL, Hughes DL, Richards RL (1995) Transition Met Chem 20:372

    Article  CAS  Google Scholar 

  35. Gabbiani C, Casini A, Messori L, Guerri A, Cinellu MA, Minghetti G, Corsini M, Rosani C, Zanello P, Arca M (2008) Inorg Chem 47:2368

    Article  PubMed  CAS  Google Scholar 

  36. Cinellu MA, Minghetti G, Pinna MV, Stoccoro S, Zucca A, Manassero M (2000) J Chem Soc Dalton Trans 1261

  37. Marcon G, Carotti S, Coronnello M, Messori L, Mini E, Orioli P, Mazzei T, Cinellu MA, Minghetti G (2002) J Med Chem 45:1672

    Article  PubMed  CAS  Google Scholar 

  38. Lu ZH, Sham TK, Vos M, Bzowski A, Mitchell JV, Norton PR (1992) Phys Rev B 45:8811

    Article  CAS  Google Scholar 

  39. Gardea-Torresdey JL, Tiemann KJ, Parson JG, Gamez G, Herrera I, Jose-Yacaman M (2002) Microchem J 71:193

    Article  CAS  Google Scholar 

  40. Penner-Hahn JE (1999) Coord Chem Rev 190–192:1101

    Article  Google Scholar 

  41. Penner-Hahn JE (2005) Coord Chem Rev 249:161

    Article  CAS  Google Scholar 

  42. Levina A, Armstrong RS, Lay PA (2005) Coord Chem Rev 249:141

    Article  CAS  Google Scholar 

  43. Ulery AL, Drees LR (eds) (2008) Methods of soil analysis—mineralogical methods. Soil Science Society of America Book Series No. 5. Madison, WI

  44. Zou J, Taylor P, Dornan J, Robinson SP, Walkinshaw MD, Sadler PJ (2000) Angew Chem Int Ed 39:2931

    CAS  Google Scholar 

  45. Hill DT, Isab AA, Griswold DE, Di Martino MJ, Matz ED, Figueroa AL, Wawro JE, DeBrosse C, Reiff WM, Elder RC, Jones B, Webb JW, Shaw CF (2010) Inorg Chem 49:7663

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the COST Action D39 for fruitful discussion and financial support. A.C.C. gratefully acknowledges the Swiss National Science Foundation (AMBIZIONE project no. PZ00P2-121933) and the Swiss Confederation COST Action D39—Accord de recherche—SER project no. C09.0027) for financial support. L.M. and C.G. gratefully acknowledge Beneficentia Stiftung and Regione Toscana (NANO-TREAT project) for financial support. We thank M.A. Cinellu (University of Sassari, Italy) for a few Auoxo6 and Aubipy samples and for valuable discussion.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy

    L. Messori & C. Gabbiani

  2. INFN-LNF, Via E. Fermi, 00044, Frascati, Italy

    A. Balerna

  3. Chimie ParisTech, Laboratoire Charles Friedel, UMR CNRS 7223, 11, rue Pierre et Marie Curie, 75231, Paris Cedex 05, France

    I. Ascone & G. Jaouen

  4. Dipartimento di Chimica Strutturale e Stereochimica Inorganica, Università degli Studi di Milano, Via G. Venezian 21, 20133, Milan, Italy

    C. Castellano

  5. Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland

    A. Casini

  6. Dipartimento di Fisica, Università Sapienza, Piazzale A. Moro 2, 00185, Rome, Italy

    C. Marchioni & A. Congiu Castellano

Authors
  1. L. Messori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Balerna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Ascone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Castellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Gabbiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Casini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Marchioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Jaouen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Congiu Castellano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to L. Messori or A. Congiu Castellano.

Additional information

Note added in proof

During the preparation of this manuscript an interesting paper appeared describing selenoauranofin, the seleno analogue of auranofin [45]. Notably, this paper reports a detailed XAS characterization of this novel gold(I) compound.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Messori, L., Balerna, A., Ascone, I. et al. X-ray absorption spectroscopy studies of the adducts formed between cytotoxic gold compounds and two major serum proteins. J Biol Inorg Chem 16, 491–499 (2011). https://doi.org/10.1007/s00775-010-0748-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-010-0748-5

Keywords

Search

Navigation