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Mononuclear η6-arene ruthenium(II) complexes with pyrazolyl–pyridazine ligands: synthesis, CT-DNA binding, reactivity towards glutathione, and cytotoxicity

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Abstract

Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N’ heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common “three-legged piano-stool” pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV–Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV–Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104 M−1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA’s minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2–39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.

Graphical abstract

Molecular docking simulations visualized the interactions of arene Ru(II) complexes with CT-DNA via minor grooving. The trends were corroborated by electrochemical and cytotoxicity data.

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Acknowledgements

We acknowledge the Department of Chemistry at Egerton University in Kenya, where the conception and synthesis of the complexes were carried out. Part of this work (characterization and cell viability studies) was partially funded by the School of Chemistry University of KwaZulu-Natal (UKZN) and the Department of Chemistry, Department of Human Biology, University of Cape Town, RSA, respectively. We thank Mrs. C. J. van Rensburg for assistance in mass spectroscopic analysis and Mr. C. Grimmer for NMR analysis.

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Authors and Affiliations

  1. Department of Chemistry, Egerton University, P.O Box 536-20115, Egerton, Kenya

    Amos K. Kanyora, Peter Ongoma & Josiah O. Omolo

  2. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Reinner O. Omondi, Athi Welsh & Gregory S. Smith

  3. Department of Human Biology, Faculty of Health Science, Observatory, University of Cape Town, Cape Town, 7925, South Africa

    Sharon Prince

  4. Department of Physical Sciences, Chuka University, P.O. Box 109-60400, Chuka, Kenya

    Joel Gichumbi

  5. School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg, 3209, South Africa

    Allen Mambanda

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Kanyora, A.K., Omondi, R.O., Ongoma, P. et al. Mononuclear η6-arene ruthenium(II) complexes with pyrazolyl–pyridazine ligands: synthesis, CT-DNA binding, reactivity towards glutathione, and cytotoxicity. J Biol Inorg Chem (2024). https://doi.org/10.1007/s00775-024-02043-3

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