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

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Cavicchiol, Mauricio [1] ; Lino Zaballa, Aline Monteiro [1] ; de Paula, Queite Antonia [1] ; Prieto, Marcela Bach [2] ; Oliveira, Carla Columbano [2] ; Civitareale, Patrizia [3] ; Ciriolo, Maria Rosa [3] ; Da Costa Ferreira, Ana Maria [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Dept Quim, Inst Quim, BR-05508000 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Dept Bioquim, Inst Quim, BR-05508000 Sao Paulo, SP - Brazil
[3] Univ Tor Vergata Roma, Dipartamento Biol, I-00133 Rome - Italy
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: INORGANICS; v. 7, n. 2 FEB 2019.
Citações Web of Science: 1

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)Cl-2] (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 degrees 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 alpha-helix structure disturbance, and formation of a stable radical species (HSA-Tyr center dot) 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 (HepG(2)) 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. (AU)

Processo FAPESP: 11/50318-1 - Desenvolvimento de compostos com interesse farmacológico ou medicinal e de sistemas para seu transporte, detecção e reconhecimento no meio biológico
Beneficiário:Ana Maria da Costa Ferreira
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/07937-8 - Redoxoma
Beneficiário:Ohara Augusto
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs