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Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and Ir(III) bearing thiabendazole complexes

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Abstract

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid–base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma–mass spectrometry (ICP–MS), both complexes are more internalized than cisplatin after 4 h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

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Acknowledgements

The authors gratefully acknowledge the financial support by “la Caixa” Banking Foundation (LCF/PR/PR12/11070003), Consejería de Educación-Junta de Castilla y León-FEDER (BU042U16-BU305P18), Ministerio de Ciencia, Innovación y Universidades (RTI2018-102040-B-100) and networking support by the COST Action CA18202.

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  1. Marta Martínez-Alonso

    Present address: Laboratory for Inorganic Chemical Biology, Institute of Chemistry for Life and Health Sciences, Chimie ParisTech, PSL University, CNRS, 75005, Paris, France

Authors and Affiliations

  1. Chemistry Department, University of Burgos, Pza. Misael Bañuelos s/n, 09001, Burgos, Spain

    Javier Santolaya, Natalia Busto, Marta Martínez-Alonso, Gustavo Espino & Begoña García

  2. Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106, Braunschweig, Germany

    Jörg Grunenberg

  3. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, viale delle Scienze, Ed. 17, 90128, Palermo, Italy

    Javier Santolaya & Giampaolo Barone

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Santolaya, J., Busto, N., Martínez-Alonso, M. et al. Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and Ir(III) bearing thiabendazole complexes. J Biol Inorg Chem 25, 1067–1083 (2020). https://doi.org/10.1007/s00775-020-01823-x

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  • DOI: https://doi.org/10.1007/s00775-020-01823-x

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