Heterobinuclear copper(II)‑platinum(II) complexes with oxindolimine ligands: Interactions with DNA, and inhibition of kinase and alkaline phosphatase proteins

Two mononuclear copper(II) compounds, [Cu(isad)(H2O)Cl]Cl 1 and [Cu(isah)(H2O)Cl]Cl 2, and its corresponding heterobinuclear species containing also platinum(II), [CuCl(isad)Pt(NH3)Cl2] 3 and [CuCl(isah)Pt(NH3)Cl2] 4 (where isad and isah are oxindolimine ligands, (E)-3-(2-(3-aminopropylamino)ethylim...

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Bibliographic Details
Published in:	Journal of inorganic biochemistry Vol. 203; p. 110863
Main Authors:	Aranda, Esther Escribano, da Luz, Juliana Silva, Oliveira, Carla Columbano, Divina Petersen, Philippe A., Petrilli, Helena M., da Costa Ferreira, Ana M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-02-2020
Subjects:	Copper DNA binding Heterobinuclear metal complexes Kinase and alkaline phosphatase inhibition Nuclease activity Platinum Nuclease activity Heterobinuclear metal complexes Kinase and alkaline phosphatase inhibition Copper Platinum DNA binding
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Summary:	Two mononuclear copper(II) compounds, [Cu(isad)(H2O)Cl]Cl 1 and [Cu(isah)(H2O)Cl]Cl 2, and its corresponding heterobinuclear species containing also platinum(II), [CuCl(isad)Pt(NH3)Cl2] 3 and [CuCl(isah)Pt(NH3)Cl2] 4 (where isad and isah are oxindolimine ligands, (E)-3-(2-(3-aminopropylamino)ethylimino)indolin-2-one, and (E)-3-(3-amino-2-hydroxypropylimino)indolin-2-one, respectively), have been previously synthesized and characterized by different spectroscopic techniques in our laboratory. Cytotoxicity assays performed with B16F10 murine cancer cells, and MES-SA human uterine sarcoma cells, showed IC50 values lower or in the same order of cisplatin. Herein, in order to better elucidate their probable modes of action, possible interaction and damage to DNA, as well as their effect on the activity of crucial proteins were verified. Both mononuclear complexes and the binuclear compound 4 displayed a significant cleavage activity toward plasmid DNA, while compound 3 tends to protect DNA from oxidative damage, avoiding degradation. Complementary experiments indicated a significant inhibition activity toward cyclin-dependent kinase (CDK1/cyclinB) activity in the phosphorylation of histone H1, and only moderate inhibition concerning alkaline phosphatase. Results also revealed that the reactivity is reliant on the ligand structure and on the nature of the metal present, in a synergistic effect. Simulation studies complemented and supported our results, indicating different bindings of the binuclear compounds to DNA. Therefore, the verified cytotoxicity of these complexes comprises multiple modes of action, including modification of DNA conformation, scission of DNA strands by reactive oxygen species, and inhibition of selected proteins that are crucial to the cellular cycle. [Display omitted] •Copper‑platinum heterobinuclear complexes were compared to analogous copper-only compounds.•Reactivity depends on ligand structure and chemical nature of metal ions.•Preferential binding to DNA occurs via platinum center, leading to structure distortion.•Damage also occurs via oxidative cleavage, caused by reactive oxygen species (ROS) formation at the copper center.•All compounds inhibit cyclin-dependent kinase more remarkably that alkaline phosphatase.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0162-0134 1873-3344
DOI:	10.1016/j.jinorgbio.2019.110863