JBIC Journal of Biological Inorganic Chemistry

, Volume 13, Issue 6, pp 909–918 | Cite as

The reduction of (ImH)[trans-RuIIICl4(dmso)(Im)] under physiological conditions: preferential reaction of the reduced complex with human serum albumin

  • Malgorzata Brindell
  • Iwona Stawoska
  • Justyna Supel
  • Andrzej Skoczowski
  • Grazyna StochelEmail author
  • Rudi van EldikEmail author
Original Paper


A systematic study of the reduction of (ImH)[trans-RuCl4(dmso)(Im)] (NAMI-A; dmso is dimethyl sulfoxide, Im is imidazole), a promising antimetastasing agent, by l-ascorbic acid under physiological conditions is reported. Under blood plasma conditions (pH 7.4, 0.1–0.15 M NaCl , 37 °C) the rapid reduction of trans-[RuIIICl4(dmso)(Im)] results in the formation of trans-[RuIICl4(dmso)(Im)]2− within seconds, and is followed by successive dissociation of the chloride ligands, whereas neither dmso nor imidazole ligands are released during the reaction. Under our experimental conditions, the formation of the ascorbate dianion is the rate-determining step, and once it has formed it reacts rapidly with NAMI-A. Moreover, the NAMI-A complex is very unstable at physiological pH (7.4); therefore, the hydrolysis of NAMI-A cannot be excluded as a competing reaction. During hydrolysis, aquated derivatives via stepwise dissociation of chloride and dmso ligands are formed, and most of these species have a higher redox potential and are expected to be even more easily reduced by ascorbic acid. Thus, it is very likely that the reduced form of NAMI-A or the reduction products of its hydrolytic derivatives react with albumin. The reaction of reduced NAMI-A with human serum albumin leads to the formation of stable adducts, with a binding efficiency very similar to that of the parent complex, viz., 3.2 ± 0.3 and 4.0 ± 0.4 mol of Ru(II) and Ru(III) per mole of albumin, respectively, however with a significantly higher reactivity.


NAMI-A Antimetastatic drug Ascorbic acid Albumin Hydrolysis 



The authors gratefully acknowledge financial support from the Deutsche Forschungsgemeinschaft (SFB 583), the European Commission for the AQUACHEM Research Training Network (contract no. MRTN-CT-2003-503864) and the Polish Ministry of Science and Higher Education (grant PB-1283/T09/2005/29). They kindly acknowledge Wiesław Knap and Halina Mrowiec for performing the ICP-MS experiments.

Supplementary material

775_2008_378_MOESM1_ESM.pdf (226 kb)
Supporting information (PDF 226 kb).


  1. 1.
    Rademaker-Lakhai JM, van_den_Bongard D, Pluim D, Beijnen JH, Schellens JHM (2004) Clin Cancer Res 10:3717–3727PubMedCrossRefGoogle Scholar
  2. 2.
    Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248PubMedCrossRefGoogle Scholar
  3. 3.
    Messori L, Kratz F, Alessio E (1996) Met Based Drugs 3:1–9PubMedCrossRefGoogle Scholar
  4. 4.
    Messori L, Orioli P, Vullo D, Alessio E, Iengo E (2000) Eur J Biochem 267:1206PubMedCrossRefGoogle Scholar
  5. 5.
    Messori L, Vilchez FG, Vilaplana R, Piccioli F, Alessio E, Keppler B (2000) Met Based Drugs 7:335PubMedCrossRefGoogle Scholar
  6. 6.
    Bergamo A, Messori L, Piccioli F, Cocchietto M, Sava G (2003) Invest New Drugs 21:401–411PubMedCrossRefGoogle Scholar
  7. 7.
    Khalaila I, Bergamo A, Bussy F, Sava G, Dyson PJ (2006) Int J Oncol 29:261–268PubMedGoogle Scholar
  8. 8.
    Ravera M, Baracco S, Cassino C, Colangelo D, Bagni G, Sava G, Osella D (2004) J Inorg Biochem 98:984–990PubMedCrossRefGoogle Scholar
  9. 9.
    Groessl M, Reisner E, Hartinger CG, Eichinger R, Semenova O, Timerbaev AR, Jakupec MA, Arion VB, Keppler BK (2007) J Med Chem 50:2185–2193PubMedCrossRefGoogle Scholar
  10. 10.
    Bacac M, Hotze ACG, van der Schilden K, Haasnoot JG, Pacor S, Alessio E, Sava G, Reedijk J (2004) J Inorg Biochem 98:402–412PubMedCrossRefGoogle Scholar
  11. 11.
    Chen J, Chen L, Liao S, Zheng K, Ji L (2007) J Phys Chem B 111:7862–7869PubMedCrossRefGoogle Scholar
  12. 12.
    Sava G, Alessio E, Bergamo A, Mestroni G (1999) In: Clarke MJ, Sadler PJ (eds) Topic in biological inorganic chemistry. Springer, Berlin, pp 143–169Google Scholar
  13. 13.
    Arrigoni O, De Tullio MC (2002) Biochim Biophys Acta 1569:1–9PubMedGoogle Scholar
  14. 14.
    Sava G, Bergamo A, Zorzet S, Gava B, Casarsa C, Cocchietto M, Furlani A, Scarcia V, Serli B, Iengo E, Alessio E, Mestroni G (2002) Eur J Cancer 38:427–435PubMedCrossRefGoogle Scholar
  15. 15.
    Ravera M, Baracco S, Cassino C, Zanello P, Osella D (2004) Dalton Trans 2347–2351Google Scholar
  16. 16.
    Brindell M, Piotrowska D, Shoukry AA, Stochel G, van_Eldik R (2007) J Biol Inorg Chem 12:809–818PubMedCrossRefGoogle Scholar
  17. 17.
    Mestroni G, Alessio E, Sava G (1998) Int Pat WO 98/00431Google Scholar
  18. 18.
    Alessio E, Balducci E, Calligaris M, Costa G, Attia WH, Mestroni G (1991) Inorg Chem 30:609–618CrossRefGoogle Scholar
  19. 19.
    Beaven GH, Chen SH, d’Albis A, Gratzer WB (1974) Eur J Biochem 41:539–546PubMedCrossRefGoogle Scholar
  20. 20.
    Fleming JE, Miyashita K, Quay SC, Bensch KG (1983) Biochem Biophys Res Commun 115:531–535PubMedCrossRefGoogle Scholar
  21. 21.
    Bouma M, Nuijen B, Jansen MT, Sava G, Flaibani A, Bult A, Beijnen JH (2002) Int J Pharm 248:239–246PubMedCrossRefGoogle Scholar
  22. 22.
    Williams NH, Yandell JK (1982) Aust J Chem 35:1133–1144Google Scholar
  23. 23.
    Martinez P, Zuluaga J, Kraft J, van Eldik R (1988) Inorg Chim Acta 146:9–12CrossRefGoogle Scholar
  24. 24.
    Williams NH, Yandell JK (1983) Aust J Chem 36:2377–2386Google Scholar
  25. 25.
    Strehlow H (1992) Rapid reactions in solutions. VCH, Weinheim, pp 103–116Google Scholar
  26. 26.
    Reisner E, Arion VB, da Silva MFCG, Lichtenecker R, Eichinger A, Keppler BK, Kukushkin VY, Pombeiro AJL (2004) Inorg Chem 43:7083–7093PubMedCrossRefGoogle Scholar
  27. 27.
    Rard JA (1985) Chem Rev 85:1–39CrossRefGoogle Scholar
  28. 28.
    Trynda-Lemiesz L, Kozlowski H, Katsaros N (2000) Met Based Drugs 7:293–299PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2008

Authors and Affiliations

  • Malgorzata Brindell
    • 1
    • 2
  • Iwona Stawoska
    • 1
  • Justyna Supel
    • 3
  • Andrzej Skoczowski
    • 4
  • Grazyna Stochel
    • 1
    Email author
  • Rudi van Eldik
    • 2
    Email author
  1. 1.Department of Inorganic Chemistry, Faculty of ChemistryJagiellonian UniversityKrakowPoland
  2. 2.Inorganic Chemistry, Department of Chemistry and PharmacyUniversity of Erlangen-NürnbergErlangenGermany
  3. 3.Department of Crystal Chemistry and Crystal Physics, Faculty of ChemistryJagiellonian UniversityKrakowPoland
  4. 4.Institute of Plant PhysiologyPolish Academy of ScienceKrakowPoland

Personalised recommendations