Antiproliferative, DNA binding, and cleavage properties of dinuclear Co(III) complexes containing the bioactive quinizarin ligand

Abstract

The adverse side effects and acquired resistance associated with the clinical application of traditional platinum-based anticancer drugs have forced investigation of alternative transition metal-based compounds and their cytostatic properties. Over the last years, the anticancer potential of cobalt complexes has been extensively studied, and in-depth analyses of their mode of action have been conducted. In this work, we present antiproliferative activity against human cancer cells of the dinuclear Co(III) complexes bearing the quinizarin ligand and tris(2-aminoethyl)amine (tren, compound 1) or tris(2-pyridylmethyl)amine (tpa, compound 2) co-ligands. To contribute the understanding mechanisms of biological action of these compounds, their association with DNA in the cells, DNA binding in cell-free media, and DNA cleavage capability were investigated in detail. The results demonstrate that both complexes interact with DNA in tumor cells. However, their mechanism of antiproliferative action is different, and this difference is mirrored by distinct antiproliferative activity. The antiproliferative effect of 1 is connected with its ability to intercalate into DNA and subsequently to inhibit activities of DNA processing enzymes. In contrast, the total antiproliferative efficiency of 2, thanks to its redox properties, appears to be connected with its ability to form radicals and, consequently, with the ability of 2 to cleave DNA. Hence, the findings presented in this study may significantly contribute to understanding the antitumor potential of cobalt complexes.

Graphic abstract

Dinuclear Co(III) complexes containing the bioactive quinizarin ligand exhibit antiproliferative activity based on distinct mechanism

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Acknowledgements

This work was supported by the Czech Science Foundation (Grant no. 18-09502S). The work of H. C. and J. P. was supported by the (Project IGA_PrF_2019_030). The research of MK, SN, and PB was supported by the EU and co-financed by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008, the Hungarian Scientific Research Fund (OTKA K112317), and the ÚNKP-19-3-I-DE-45, ÚNKP-19-3-I-DE-56 New National Excellence Program of the Ministry for Innovation and Technology (Hungary).

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JK designed research; HC, HK, JP, and JK performed experiments and analyzed data; MK, SN, and PB supplied cobalt complexes and measured NMR spectra; VB and JK wrote the manuscript; all authors reviewed and approved the manuscript.

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Correspondence to Jana Kasparkova.

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Crlikova, H., Kostrhunova, H., Pracharova, J. et al. Antiproliferative, DNA binding, and cleavage properties of dinuclear Co(III) complexes containing the bioactive quinizarin ligand. J Biol Inorg Chem 25, 339–350 (2020). https://doi.org/10.1007/s00775-020-01765-4

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Keywords

  • Cobalt
  • Quinizarin
  • Antiproliferative activity
  • DNA
  • Radicals