Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and
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ORIGINAL PAPER
Experimental and theoretical characterization of the strong effects on DNA stability caused by half‑sandwich Ru(II) and Ir(III) bearing thiabendazole complexes Javier Santolaya1,3 · Natalia Busto1 · Marta Martínez‑Alonso1,4 · Gustavo Espino1 · Jörg Grunenberg2 · Giampaolo Barone3 · Begoña García1 Received: 12 June 2020 / Accepted: 31 August 2020 © Society for Biological Inorganic Chemistry (SBIC) 2020
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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00775-020-01823-x) contains supplementary material, which is available to authorized users. * Natalia Busto [email protected] 1
Chemistry Department, University of Burgos, Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
2
Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
3
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, viale delle Scienze, Ed. 17, 90128 Palermo, Italy
4
Present Address: Laboratory for Inorganic Chemical Biology, Institute of Chemistry for Life and Health Sciences, Chimie ParisTech, PSL University, CNRS, 75005 Paris, France
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Vol.:(0123456789)
JBIC Journal of Biological Inorganic Chemistry
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