Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

Castelli, Silvia; Gonçalves, Marcos Brown; Katkar, Prafulla; Stuchi, Gabriela Cristina; Couto, Ricardo Alexandre Alves de; Petrilli, Helena Maria; Ferreira, Ana Maria da Costa

doi:10.1016/j.jinorgbio.2018.05.012

Cited by 24 publications

(13 citation statements)

References 49 publications

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“…All the structures of CuC Top1 inhibitors are reported in Figure 2 and the main characteristics in Table 1 . Oxindolimine-Cu(II) Top1 inhibitors such as 1 are planar copper compounds [ 70 ] that do not permit enzyme-DNA complex formation [ 71 , 72 , 73 ]. Besides, they produce ROS [ 70 ].…”

Section: Copper Complexes As Topoisomerases Inhibitorsmentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

131

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Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

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Section: Copper Complexes As Topoisomerases Inhibitorsmentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

131

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“…These data can also be indicative of alternative targets inside the cell in addition to DNA, in a process modulated by the metal ion, by the ligand, as well as by the predominant metal-ligand species formed. This class of metal complexes has already shown good inhibition activity toward kinases [31] and topoisomerases [32], and the remarkable ability to damage mitochondria [30].…”

Section: Discussionmentioning

confidence: 98%

“…In more recent studies, a significant inhibition of crucial proteins, kinase (CDK1/cyclin B) [31] and topoisomerase IB [32], was additionally verified, emphasizing the contribution of the ligand to the reactivity of such complexes, and their behavior as multifunctional compounds. Interactions of the ligands at the active cavity of the proteins, mostly through hydrogen bonds and stacking, modulate the activity of such complexes [31,32]. These compounds exhibited high thermodynamic stability when tested using human serum albumin (has) as a competitive biological ligand.…”

Section: Introductionmentioning

confidence: 91%

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

et al. 2019

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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.

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“…Em nossos estudos com complexos de cobre(II) antitumorais, identificamos topoisomerase IB (topo I) [81,82] e quinases dependentes de ciclinas (CDK1 e CDK2) como possíveis alvos [83], além de ácidos nucleicos. Outras proteínas já foram descritas como potenciais alvos, como a proteasoma 26S, em estudos de complexos de cobre(I) com ligantes derivados de tris(pirazolil)borato.…”

Section: Mecanismos De Ação Antitumoralunclassified

Avaliação da potencialidade e dos mecanismos de ação de complexos dinucleares de cobre como agentes terapêuticos antitumorais

Nunes¹

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Primeiramente agradeço a Deus que, com sua infinita misericórdia, permitiu que esse trabalho fosse desenvolvido e concluído, me renovando a força que em muitos momentos perdi. Ao meu Bom Jesus de Pirapora, que me trouxe a fé necessária para não me perder no caminho, e a minha mãe Nossa Senhora Aparecida. À querida Profª Ana Maria da Costa Ferreira, pela orientação, amizade e companheirismo, por ter aceitado me orientar de bom coração desde o primeiro contato, e me auxiliar com sua experiência e motivação. Além de compreender quando as coisas pareciam não fluir. Ao Prof. Marius Réglier, por sua experiência. Ao Dr. Roger Chammas, e suas colaboradoras Dra. Andréia Otake e Dra. Silvina Bustos do Instituto do Câncer do Estado de São Paulo-ICESP (Faculdade de Medicina da USP), por seu auxílio, experimentações no instituto, pelos comentários, discussões, esclarecimentos e sugestões, sem as quais esse trabalho não teria rendido os bons frutos que rendeu, e principalmente pela oportunidade de aprender a manusear e entender melhor o mundo das células e a rotina de trabalho dentro desta tão importante instituição.

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Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

Cited by 24 publications

References 49 publications

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

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

Avaliação da potencialidade e dos mecanismos de ação de complexos dinucleares de cobre como agentes terapêuticos antitumorais

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