Thiosemicarbazone N-Heterocyclic Cu(II) complexes inducing nuclei DNA and mitochondria damage in hepatocellular carcinoma cells

Zhang, Siye; Zhao, Jinan; Guo, Yan; Hu, Jingyu; Chen, Xiaojing; Ruan, Hehui; Cao, T.; Hou, Hongwei

doi:10.1016/j.jinorgbio.2022.111964

Cited by 5 publications

(7 citation statements)

References 50 publications

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“…Various studies have revealed that copper complexes could break or intercalate the DNA and serve as artificial metallonucleases, [57][58][59][60] which are capable of cleaving nucleic acids, resulting in either loss of genetic integrity or overactivation of DNA damage repair mechanisms and ultimately apoptosis, to execute anti-cancer effects. [61][62][63] Copper complexes have been found to noncovalently interact with DNA double helix other than bind with DNA covalently. The noncovalent DNA interactions included intercalative, electrostatic, and groove binding of metal complexes along the major or minor DNA groove.…”

Section: Copper Complexes Target Dnamentioning

confidence: 99%

Copper and Copper Complexes in Tumor Therapy

Wang,

Tang,

Yuan

et al. 2024

ChemMedChem

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Copper (Cu), a crucial trace element in physiological processes, has garnered significant interest for its involvement in cancer progression and potential therapeutic applications. The regulation of cellular copper levels is essential for maintaining copper homeostasis, as imbalances can lead to toxicity and cell death. The development of drugs that target copper homeostasis has emerged as a promising strategy for anticancer treatment, with a particular focus on copper chelators, copper ionophores, and novel copper complexes. Recent research has also investigated the potential of copper complexes in cancer therapy.

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Section: Copper Complexes Target Dnamentioning

confidence: 99%

Copper and Copper Complexes in Tumor Therapy

Wang,

Tang,

Yuan

et al. 2024

ChemMedChem

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“…Gou et al synthesised an Fe(III) complex (5) with an α-N-heterocyclic thiocarbazone ligand, which showed relatively strong redox activity, with an Fe(III/II) redox potential similar to that of cellular oxidants and reducing agents ( Gou et al, 2016 ). Zhang et al synthesised two α-N-heterocyclic thiosemicarbazone Cu(II) complexes (6 and 7), which showed superlative in vitro inhibitory activity against HCC (human lung adenocarcinoma) cell lines with IC 50 values of 0.2 and 2 μM, respectively ( Zhang et al, 2022 ). Gu et al successfully synthesised two copper complexes (8 and 9) from N-heterocyclic thiosemicarbazone and CuBr 2 that exhibited remarkable anticancer and anti-metastasis activities ( Gu et al, 2019 ).…”

Section: Design Principles and Structural Diversitymentioning

confidence: 99%

“…Zhang et al found that the conformation of DNA can be altered or distorted by copper complexes that bind to DNA mainly in a groove pattern. Two of these complexes cause severe mitochondrial damage by elevating ROS and Ca 2+ levels, lowering both adenosine triphosphate (ATP) levels and mitochondrial membrane potential (Δψm), and altering mitochondrial morphology ( Zhang et al, 2022 ). Using confocal fluorescence imaging, Gu et al determined that complex 9 primarily accumulates in the mitochondria and promotes HeLa cell apoptosis by reducing the mitochondrial membrane potential and inducing ROS production ( Gu et al, 2019 ).…”

Section: Anti-tumour Mechanisms Targeting Mitochondrial Pathwaysmentioning

confidence: 99%

Recent progress in thiocarbazone metal complexes for cancer therapy via mitochondrial signalling pathway

Zheng,

An,

et al. 2024

Front. Chem.

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Mitochondria are the energy factories of cells and are important targets for the development of novel tumour treatment strategies owing to their involvement in processes such as apoptosis, oxidative stress, and metabolic programming. Thiosemicarbazone metal complexes target mitochondria and reduce mitochondrial membrane potential. The breakdown of mitochondrial membrane potential is a key event in the early stage of apoptosis, which releases cytochrome C and other pro-apoptotic factors, activates the intracellular apoptotic enzyme cascade, and eventually causes irreversible apoptosis of tumour cells. Thiosemicarbazone metal complexes targeting the mitochondria have recently emerged as potential antitumour agents; therefore, this review describes the structural diversity of thiosemicarbazone metal [Fe(III), Cu(II), Ni(II), Zn(II), Ga(III), Pb(II), Au(III), and Ir(III)] complexes and explores their anti-tumour mechanisms that target mitochondrial pathways.

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“…Current efforts to further optimize the pharmacological profile of 2-formylpyridine TSCs and their copper(II) complexes is well documented in the literature. − Recently, we reported that TSC proligands with a morpholine moiety attached at the δ-position of the pyridine ring and their copper(II) complexes display stronger antiproliferative activity than Triapine, even though their mouse R2 (mR2) RNR inhibitory activity in the presence of dithiothreitol (DTT) was only moderate . In addition, Triapine analogues with a redox active amino-dimethylphenol moiety at the terminal nitrogen atom of the TSC scaffold showed cytotoxicity in cancer cells with low μM IC 50 values.…”

Section: Introductionmentioning

confidence: 99%

Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters

Milunovic,

Ohui,

Besleaga

et al. 2024

J. Med. Chem.

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The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H 2 L 3 –H 2 L 6 , with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3–6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y•) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

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Thiosemicarbazone N-Heterocyclic Cu(II) complexes inducing nuclei DNA and mitochondria damage in hepatocellular carcinoma cells

Cited by 5 publications

References 50 publications

Copper and Copper Complexes in Tumor Therapy

Copper and Copper Complexes in Tumor Therapy

Recent progress in thiocarbazone metal complexes for cancer therapy via mitochondrial signalling pathway

Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters

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