DNA binding, cleavage, apoptosis and cytotoxicity studies of three heteroleptic nickel complexes bearing β-diketones

• Published in: Inorganica Chimica Acta Vol. 511; p. 119824
• Main Authors: Sousa, Luana M., Souza, Wesley A., Paixão, Drielly A., Fazzi, Rodrigo B., Tezuka, Daiane Y., Lopes, Carla D., Carneiro, Zumira A., Moreira, Mariete B., Pivatto, Marcos, Netto, Adelino V.G., de Albuquerque, Sérgio, Ferreira, Francis B., De Oliveira, Ronaldo J., Resende, Jackson A.L.C., Lino, Ricardo C., De Oliveira Júnior, Robson J., Da Costa Ferreira, Ana M., Guerra, Wendell
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-10-2020; Elsevier Science Ltd
• Subjects: Anions; Anticancer properties; Apoptosis; Binding; Cancer; Chelation; Cleavage; Coordination compounds; Crystal structure; Deoxyribonucleic acid; Dichroism; Diketones; DNA; DNA binding; DNA cleavage; Fluorescence; Grooves; Hydrogen peroxide; Magnetic permeability; Molecular docking; Nickel; Nickel complexes; Nitrogen atoms; Oxygen atoms; Plasmids; Single crystals; Toxicity; β-diketones; β-diketones; Nickel complexes; DNA cleavage; DNA binding; Apoptosis; Cancer
• ISSN: 0020-1693; 1873-3255
• DOI: 10.1016/j.ica.2020.119824

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•NiII complexes are capable of binding in the minor groove of DNA.•DNA cleavage was observed.•Two NiII complexes were more active than cisplatin toward cancer cell lines.•Two NiII complexes induced late apoptosis.
In this work, three nickel(II) complexes, namely, [Ni(η2-NO3)(bta)(phen)] (I), [Ni(η2-NO3)(btc)(phen)] (II), and [Ni(η2-NO3)(btf)(phen)] (III) (bta = 4,4,4-trifluoro-1-phenyl-1,3-butanedione anion, btc = 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione anion, btf = 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione anion, phen = 1,10-phenanthroline) were prepared and fully characterized by magnetic susceptibility measurements, spectroscopic methods and single-crystal X-ray diffraction. The spectral and structural data confirm that the β-diketones anions coordinate via the oxygen atoms, whilst the heterocyclic base coordinates through the nitrogen atoms. A nitrate coordinated in bidentate mode completes the coordination sphere around the metal center. The anticancer activity of chelating ligands and their nickel complexes was evaluated against two tumor cell lines, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). The complexes I and II were more active than cisplatin and interacted more effectively with DNA, with Kb values in the range of 103 –104 M−1. According to data from circular dichroism (CD) and fluorescence spectroscopy, these complexes appear to bind to the DNA groove and/or by electrostatic forces. Molecular docking followed by semiempirical simulations reinforce that they are capable of binding in the minor groove of the double helix of ct-DNA in an A-T rich region. DNA cleavage studies indicated that the complex II cleaves the plasmid DNA in the presence of H2O2. Subsequently, we found that I and II induce late apoptosis in MCF-7 cells.