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

Maurício Cavicchioli,Aline Zaballa,Ana Da Costa Ferreira,Patrizia Civitareale,Maria Ciriolo,Carla Oliveira,Queite Paula,Marcela Prieto

doi:10.3390/inorganics7020012

Maurício Cavicchioli, Aline Zaballa + Show 6 more

Open Access

https://doi.org/10.3390/inorganics7020012

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Abstract

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.

Highlights

Cancer is a very important cause of death globally, according to the World Health Organization (WHO) [1]
For complexes of redox active metal ions, such as iron or copper, oxidative stress plays an important rule, usually causing single and double strand scission by reactive oxygen species (ROS), and can lead to a wide array of DNA lesions implicated in the etiology of many human diseases [5]
We have investigated a series of oxindolimine–metal complexes as pro-apoptotic compounds toward different2019, tumor trying to elucidate

Summary

Introduction

Cancer is a very important cause of death globally, according to the World Health Organization (WHO) [1]. It corresponds to a large group of diseases, affecting different organs, with slow through to very quick progression. Different targets have been identified in wide-ranging studies, depending on the metal and on the ligand. For complexes of redox active metal ions, such as iron or copper, oxidative stress plays an important rule, usually causing single and double strand scission by reactive oxygen species (ROS), and can lead to a wide array of DNA lesions implicated in the etiology of many human diseases [5]

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