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

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. 1 H NMR and acid–base studies have shown that aquo-complexes are the reactive s...

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Bibliographic Details
Published in:Journal of biological inorganic chemistry 2020-12, Vol.25 (8), p.1067-1083
Main Authors: Santolaya, Javier, Busto, Natalia, Martínez-Alonso, Marta, Espino, Gustavo, Grunenberg, Jörg, Barone, Giampaolo, García, Begoña
Format: Article
Language:English
Subjects:
Adenocarcinoma
Biochemistry
Biomedical and Life Sciences
Cell culture
Circular dichroism
Cisplatin
Colon
Computer applications
Cytoplasm
Cytotoxicity
Denaturation
Deoxyribonucleic acid
DNA
DNA structure
Enantiomers
Inorganic chemistry
Life Sciences
Ligands
Localization
Mass spectroscopy
Microbiology
NMR
Nuclear magnetic resonance
Original Paper
Protein structure
Secondary structure
Thermal stability
Thiabendazole
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Summary: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. 1 H 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. Graphic abstract
ISSN:0949-8257
1432-1327
DOI:10.1007/s00775-020-01823-x