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Open AccessArticle

Oxidative Assets Toward Biomolecules and Cytotoxicity of New Oxindolimine-Copper(II) and Zinc(II) Complexes

1
Departamento de Química, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, SP, Brazil
2
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo 05508-000, SP, Brazil
3
Dipartamento di Biologia, Università Tor Vergata di Roma, 00133 Roma, Italy
*
Author to whom correspondence should be addressed.
Inorganics 2019, 7(2), 12; https://doi.org/10.3390/inorganics7020012
Received: 30 October 2018 / Revised: 11 January 2019 / Accepted: 17 January 2019 / Published: 26 January 2019
A new oxindolimine ligand derived from isatin (1H-indole-2,3-dione) and 2-aminomethylbenzimidazole was synthesized, leading to two novel complexes after metalation with copper(II) perchlorate or zinc(II) chloride, [Cu(isambz)2](ClO4)2 (complex 1) and [Zn(isambz)Cl2] (complex 2). This new ligand was designed as a more lipophilic compound, in a series of oxindolimine–metal complexes with antitumor properties, having DNA, mitochondria, and some proteins, such as CDK1 kinase and topoisomerase IB, as key targets. The new complexes had their reactivity to human serum albumin (HSA) and DNA, and their cytotoxicity toward tumor cells investigated. The binding to CT-DNA was monitored by circular dichroism (CD) spectroscopy and fluorescence measurements using ethidium bromide in a competitive assay. Consequent DNA cleavage was verified by gel electrophoresis with complex 1, in nmolar concentrations, with formation of linear DNA (form III) after 60 min incubation at 37 °C, in the presence of hydrogen peroxide, which acts as a reducing agent. Formation of reactive oxygen species (ROS) was observed, monitored by spin trapping EPR. Interaction with HSA lead to α-helix structure disturbance, and formation of a stable radical species (HSA–Tyr·) and carbonyl groups in the protein. Despite showing oxidative ability to damage vital biomolecules such as HSA and DNA, these new complexes showed moderate cytotoxicity against hepatocellular carcinoma (HepG2) and neuroblastoma (SHSY5Y) cells, similarly to previous compounds in this series. These results confirm DNA as an important target for these compounds, and additionally indicate that oxidative damage is not the leading mechanism responsible for their cytotoxicity. Additionally, this work emphasizes the importance of ligand characteristics and of speciation in activity of metal complexes. View Full-Text
Keywords: isatin-derived ligands; oxindolimine–metal complexes; DNA cleavage; HSA oxidation; cytotoxicity; antiproliferative activity isatin-derived ligands; oxindolimine–metal complexes; DNA cleavage; HSA oxidation; cytotoxicity; antiproliferative activity
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Cavicchioli, M.; Zaballa, A.M.L.; Paula, Q.A.; Prieto, M.B.; Oliveira, C.C.; Civitareale, P.; Ciriolo, M.R.; Da Costa Ferreira, A.M. Oxidative Assets Toward Biomolecules and Cytotoxicity of New Oxindolimine-Copper(II) and Zinc(II) Complexes. Inorganics 2019, 7, 12.

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