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Open AccessArticle

Copper(II) Complexes with Tetradentate Piperazine-Based Ligands: DNA Cleavage and Cytotoxicity

1
Institut für Chemie und Biochemie, Freie Universität Berlin, Fabeckstr. 34/36, 14195 Berlin, Germany
2
Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA
3
Institut für Anorganische Chemische, Technische Universität Graz, Stremayrgasse 9/V, A-8010 Graz, Austria
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Institut für Physikalische und Theoretische Chemie, Technische Universität Graz, Stremayrgasse 9/II, A-8010 Graz, Austria
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Institut für Chemie, Otto-von-Guericke-Universität Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany
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Department of Chemistry, Faculty of Science, Alexandria University, Moharem Bey, 21511 Alexandria, Egypt
*
Authors to whom correspondence should be addressed.
Received: 2 December 2020 / Revised: 27 December 2020 / Accepted: 29 December 2020 / Published: 1 February 2021
(This article belongs to the Special Issue Metal Complexes with Biological Functions)
Five-coordinate Cu(II) complexes, [Cu(Ln)X]ClO4/PF6, where Ln = piperazine ligands bearing two pyridyl arms and X = ClO4 for Ln = L1 (1-ClO4), L2 (2-ClO4), L3 (3-ClO4), and L6 (6-ClO4) as well as [Cu(Ln)Cl]PF6 for Ln = L1 (1-Cl), L4 (4-Cl), and L5 (5-Cl) have been synthesized and characterized by spectroscopic techniques. The molecular structures of the last two complexes were determined by X-ray crystallography. In aqueous acetonitrile solutions, molar conductivity measurements and UV-VIS spectrophotometric titrations of the complexes revealed the hydrolysis of the complexes to [Cu(Ln)(H2O)]2+ species. The biological activity of the Cu(II) complexes with respect to DNA cleavage and cytotoxicity was investigated. At micromolar concentration within 2 h and pH 7.4, DNA cleavage rate decreased in the order: 1-Cl1-ClO4 > 3-ClO42-ClO4 with cleavage enhancements of up to 23 million. Complexes 4-Cl, 5-Cl, and 6-ClO4 were inactive. In order to elucidate the cleavage mechanism, the cleavage of bis(4-nitrophenyl)phosphate (BNPP) and reactive oxygen species (ROS) quenching studies were conducted. The mechanistic pathway of DNA cleavage depends on the ligand’s skeleton: while an oxidative pathway was preferable for 1-Cl/1-ClO4, DNA cleavage by 2-ClO4 and 3-ClO4 predominantly proceeds via a hydrolytic mechanism. Complexes 1-ClO4, 3-ClO4, and 5-Cl were found to be cytotoxic against A2780 cells (IC50 30–40 µM). In fibroblasts, the IC50 value was much higher for 3-ClO4 with no toxic effect. View Full-Text
Keywords: copper; DNA cleavage; phosphodiester; cytotoxicity; piperazine copper; DNA cleavage; phosphodiester; cytotoxicity; piperazine
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MDPI and ACS Style

Doniz Kettenmann, S.; Nossol, Y.; Louka, F.R.; Legrande, J.R.; Marine, E.; Fischer, R.C.; Mautner, F.A.; Hergl, V.; Kulak, N.; Massoud, S.S. Copper(II) Complexes with Tetradentate Piperazine-Based Ligands: DNA Cleavage and Cytotoxicity. Inorganics 2021, 9, 12. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics9020012

AMA Style

Doniz Kettenmann S, Nossol Y, Louka FR, Legrande JR, Marine E, Fischer RC, Mautner FA, Hergl V, Kulak N, Massoud SS. Copper(II) Complexes with Tetradentate Piperazine-Based Ligands: DNA Cleavage and Cytotoxicity. Inorganics. 2021; 9(2):12. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics9020012

Chicago/Turabian Style

Doniz Kettenmann, Sebastian; Nossol, Yvonne; Louka, Febee R.; Legrande, Julia R.; Marine, Elise; Fischer, Roland C.; Mautner, Franz A.; Hergl, Vinja; Kulak, Nora; Massoud, Salah S. 2021. "Copper(II) Complexes with Tetradentate Piperazine-Based Ligands: DNA Cleavage and Cytotoxicity" Inorganics 9, no. 2: 12. https://0-doi-org.brum.beds.ac.uk/10.3390/inorganics9020012

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