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Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

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Abstract

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration–UV–vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K 1′ = 5.3–5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

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Abbreviations

BGE:

Background electrolyte

BR:

Bilirubin

CE:

Capillary electrophoresis

CZE:

Capillary zone electrophoresis

DG:

Dansylglycine

HMM:

High molecular mass

HSA:

Human serum albumin

KP1019:

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]

KP1339:

Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]

LMM:

Low molecular mass

NAMI-A:

Imidazolium trans-[tetrachlorido(dimethyl sulfoxide)(1H-imidazole)ruthenate(III)]

WF:

Warfarin

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Acknowledgments

This work was supported by the Hungarian Research Foundation OTKA K77833 and “TÁMOP-4.2.1/B-09/1/KONV-2010-0005—Creating the Center of Excellence at the University of Szeged,” cofinanced by the European Regional Fund. E.A.E. gratefully acknowledges the financial support from a J. Bolyai Research Fellowship. We thank the Austrian Science Fund (FWF; I496-B11), and COST D39 and CM0902 for financial support.

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Authors and Affiliations

  1. Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary

    Orsolya Dömötör, Tamás Kiss & Eva A. Enyedy

  2. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Christian G. Hartinger

  3. Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090, Vienna, Austria

    Christian G. Hartinger, Anna K. Bytzek & Bernhard K. Keppler

  4. Bioinorganic Chemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary

    Tamás Kiss

Authors
  1. Orsolya Dömötör
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  2. Christian G. Hartinger
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  3. Anna K. Bytzek
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  4. Tamás Kiss
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  5. Bernhard K. Keppler
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  6. Eva A. Enyedy
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Correspondence to Christian G. Hartinger or Eva A. Enyedy.

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Dömötör, O., Hartinger, C.G., Bytzek, A.K. et al. Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies. J Biol Inorg Chem 18, 9–17 (2013). https://doi.org/10.1007/s00775-012-0944-6

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  • DOI: https://doi.org/10.1007/s00775-012-0944-6

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