Synthesis, characterization and in vitro cytotoxicity of ruthenium(II) metronidazole complexes: Cell cycle arrest at G1/S transition and apoptosis induction in MCF-7 cells

Candido, Caio Cesar; Silva, Henrique Vieira Reis; Zavan, Bruno; Ionta, Marisa; Barbosa, Marília Imaculada Frazão

doi:10.1016/j.jinorgbio.2022.112022

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…It should be mentioned that the arene binuclear ruthenium complexes showed comparably greater activity than the Ru-polypyridyl complexes in inducing apoptosis in HeLa cells and showed equipotent action with the ruthenium complexes attached with 2-(2′-pyridyl)pyrimidine-4-carboxylic acid and dipyrido[3,2-a:2′,3′-c]phenazine. However, the same complexes triggered more apoptotic cell death than the monoruthenium metronidazole complexes in MCF-7 cells …”

Section: Resultsmentioning

confidence: 94%

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes

Thangavel,

Mohamed Kasim,

Rengan

2024

Inorg. Chem.

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A new set of binuclear arene ruthenium complexes [Ru2(p-cymene)2(k4-N2OS)(L1-L3)Cl2] (Ru 2 L1–Ru 2 L3) encompassing furan-2-carboxamide-based aroylthiourea derivatives (H 2 L1–H 2 L3) was synthesized and characterized by various spectral and analytical techniques. Single-crystal XRD analysis unveils the N^O and N^S mixed monobasic bidentate coordination of the ligands constructing N, S, Cl/N, O, and Cl legged piano stool octahedral geometry. DFT analysis demonstrates the predilection for the formation of stable arene ruthenium complexes. In vitro antiproliferative activity of the complexes was examined against human cervical (HeLa), breast (MCF-7), and lung (A549) cancerous and noncancerous monkey kidney epithelial (Vero) cells. All the complexes are more efficacious against HeLa and MCF-7 cells with low inhibitory doses (3.86–11.02 μM). Specifically, Ru 2 L3 incorporating p-cymene and -OCH3 fragments exhibits high lipophilicity, significant cytotoxicity against cancer cells, and lower toxicity on noncancerous cells. Staining analysis indicates the apoptosis-associated cell morphological changes expressively in MCF-7 cells. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) analyses reveal that Ru 2 L3 can raise ROS levels, reduce MMP, and trigger mitochondrial dysfunction-mediated apoptosis. The catalytic oxidation of glutathione (GSH) to its disulfide form (GSSG) by the complexes may simultaneously increase the ROS levels, alluding to their observed cytotoxicity and apoptosis induction. Flow cytometry determined the quantitative classification of late apoptosis and S-phase arrest in MCF-7 and HeLa cells. Western blotting analysis confirmed that the complexes promote apoptosis by upregulating Caspase-3 and Caspase-9 and downregulating BCL-2. Molecular docking studies unfolded the strong binding affinities of the complexes with VEGFR2, an angiogenic signaling receptor, and BCL2, Cyclin D1, and HER2 proteins typically overexpressed on tumor cells.

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Section: Resultsmentioning

confidence: 94%

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes

Thangavel,

Mohamed Kasim,

Rengan

2024

Inorg. Chem.

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“…[30][31][32] The above-mentioned different mechanisms of action, ligand substitution kinetics, and various oxidation states contributed to potential redox activity, lower toxic effect, and higher cellular uptake efficiency give advantages to ruthenium and iridium complexes over platinum-based compounds. [33][34][35] Currently, two piano-stool ruthenium(II) complexes Ru(η 6 -pcymene)Cl 2 PPh 2 CH 2 OH (RuPOH) and Ru(η 6 -p-cymene)Cl 2 P(p-OCH 3 Ph) 2 CH 2 OH (RuMPOH) and two half-sandwich iridium(III) complexes Ir(η 5 -Cp*)Cl 2 PPh 2 CH 2 OH (IrPOH) and Ir(η 5 -Cp*)Cl 2 P(p-OCH 3 Ph) 2 CH 2 OH (IrMPOH) have been synthesized, physiochemically characterized and evaluated in vitro in terms of their potential anticancer activity in our research groups. [36] We concluded that all the studied complexes undergo slow hydrolysis and the complexes with the methoxy group on the phenyl rings can catalyze the oxidation of NADH to NAD + with higher efficiency than complexes without this group.…”

Section: Introductionmentioning

confidence: 99%

Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes

Wojtala,

Komarnicka,

Kyzioł

et al. 2023

Eur J Inorg Chem

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Two piano‐stool ruthenium(II) complexes Ru(η6‐p‐cymene)Cl2PPh2CH2OH (RuPOH) and Ru(η6‐p‐cymene)Cl2P(p‐OCH3Ph)2CH2OH (RuMPOH) and two half‐sandwich iridium(III) complexes Ir(η5‐Cp*)Cl2PPh2CH2OH (IrPOH) and Ir(η5‐Cp*)Cl2P(p‐OCH3Ph)2CH2OH (IrMPOH) have been studied in terms of potential anticancer activity on previously selected cell line (human lung adenocarcinoma). Based on experimental results obtained in monoculture in vitro model mechanistic considerations on the possible cellular modes of action have been carried out. ICP‐MS analysis revealed the higher cellular uptake for less hydrophobic Ir(III) complexes in comparison to the corresponding Ru(II) compounds. Cytometric analysis showed a predominance of apoptosis over the other types of cell death for all complexes. The apoptotic pathway was confirmed by a decrease in mitochondrial membrane potential and the activation of caspases‐3/9 for both Ru(II) and Ir(III) complexes. It was concluded that in the case of Ru(II) complexes the intense ROS generation is mainly responsible for the resulting cytotoxicity. The corresponding Ir(III) complexes trigger simultaneously at least three different cytotoxic pathways i.e., depletion of mitochondrial potential, activation of caspases‐dependent apoptosis, and ROS‐associated oxidation. Thus, it can be assumed that the final accumulation of toxic effects over time via parallel activation of different pathways results in the highest cytotoxicity in vitro exhibited by Ir(III) complexes when compared with Ru(II) complexes.

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The nicotinamide ruthenium(II) complex induces the production of reactive oxygen species (ROS), cell cycle arrest, and apoptosis in melanoma cells

Silva

Zavan

et al. 2023

Polyhedron

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Synthesis, characterization and in vitro cytotoxicity of ruthenium(II) metronidazole complexes: Cell cycle arrest at G1/S transition and apoptosis induction in MCF-7 cells

Cited by 3 publications

References 46 publications

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes

Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes

The nicotinamide ruthenium(II) complex induces the production of reactive oxygen species (ROS), cell cycle arrest, and apoptosis in melanoma cells

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