Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(<scp>ii</scp>)-p-cymene complexes with acylthiourea ligands—in vitro and in vivo studies

Swaminathan, Srividya; Haribabu, Jebiti; Subarkhan, Mohamed Kasim Mohamed; Gayathri, D.; Balakrishnan, Nithya; Bhuvanesh, Nattamai; Echeverría, César; Karvembu, Ramasamy

doi:10.1039/d1dt02611a

Cited by 71 publications

(32 citation statements)

References 67 publications

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“…This bond distance was shorter in the case of Ru(II)−benzene (2.590−2.622 Å) complexes containing bidentate acylthiourea ligands over their Ru(II)−p-cymene (2.642−2.839 Å) counterparts with monodentate acylthiourea ligands as well as the uncoordinated ligands (2.660−2.681 Å). 14 The H-bond length had negligible changes in B1 (2.621 Å) and B2 (2.622 Å), however became shorter in the case of B4 (2.590 Å), indicating that the alkyl chain length difference at the Cterminal had a greater influence over the aromatic conjugation at the N-terminal. The structural alterations between the Ru− p-cymene complexes (P2 and P4) (monodentate) and the Ru−benzene (B2 and B4) (bidentate) complexes were quite significant.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The structural alterations between the Ru− p-cymene complexes (P2 and P4) (monodentate) and the Ru−benzene (B2 and B4) (bidentate) complexes were quite significant. 14 CS bond angle was higher in the case of P2 (120.18°) and P4 (120.86°) over B2 (108.93°) and B4 (109.33°). 14 These changes indicated that the ligand underwent configurational changes to accommodate a four-membered ring system within the complex structure.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…14 CS bond angle was higher in the case of P2 (120.18°) and P4 (120.86°) over B2 (108.93°) and B4 (109.33°). 14 These changes indicated that the ligand underwent configurational changes to accommodate a four-membered ring system within the complex structure. Although the effects of arene and coordination mode variation were clearly seen, it was also evident from the collected data that the terminal substituents in the acylthiourea ligand influenced both the Ru−p-cymene and Ru−benzene complexes in a similar manner.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Coordination Behavior of Acylthiourea Ligands in Their Ru(II)–Benzene Complexes─Structures and Anticancer Activity

et al. 2022

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Acylthiourea ligands have applications in both synthetic and applied chemistry. The skeleton of the ligand contains several heteroatoms which offer variable coordination modes in their complexes. Herein, we report one such erratic behavior of these types of complexes upon crystallization. Six Ru(II)–benzene complexes (B1–B6) containing the acylthiourea ligand were synthesized and adequately characterized using analytical and spectroscopic techniques. In contrast to the spectroscopic data confirming the monodentate coordination of the ligands to the Ru(II) ion, the bidentate version in the crystal structure of their Ru(II)–benzene complexes was observed. To the best of our knowledge, this is the only report as of now on N,S-coordinated acylthiourea ligands forming a four-membered ring in Ru(II)–benzene complexes, while the same ligands in the Ru(II)–p-cymene system showed a monodentate coordination. The complexes (B1–B6) exhibited good anticancer potential in A549, overcame cisplatin resistance in cisRA549, but unfortunately exhibited toxicity toward normal human umbilical vein endothelial cell lines. An increase in chain length at the C-terminal and the conjugation at the N-terminal of the acylthiourea ligands seemed to improve the cytotoxic profile of the complexes. 5-Ethynyl-2′-deoxyuridine staining helped to visualize the interruption of DNA synthesis by the active complexes B4 and B5, which was further authenticated using flow cytometry, wherein the complexes arrested the cell cycle in the S phase. The latter also proved the apoptosis mode of cell death induced by the active complexes, and the morphological changes due to apoptosis were visualized using acridine orange/ethidium bromide staining.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Coordination Behavior of Acylthiourea Ligands in Their Ru(II)–Benzene Complexes─Structures and Anticancer Activity

et al. 2022

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“…Moreover, Paltan Laha with co-authors came to the same conclusion while investigating several mononuclear cyclometalatediridium(III) complexes towards the human breast cancer cell line (MCF-7) [45]. On the other hand, Swaminathan and her team came to a different conclusion after studying six novel Ru(II)-p-cymene complexes with various acylthiourea ligands against A549 and A549cisR cancer cell lines, as in this case-longer hydrocarbon chain improves the cytotoxicity [46]. Furthermore, in the literature, the copper(II) complexes with phen and alkyl chains with different lengths as ligands show the same pattern [47].…”

Section: Introductionmentioning

confidence: 87%

Two out of Three Musketeers Fight against Cancer: Synthesis, Physicochemical, and Biological Properties of Phosphino CuI, RuII, IrIII Complexes

et al. 2022

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Two novel phosphine ligands, Ph2PCH2N(CH2CH3)3 (1) and Ph2PCH2N(CH2CH2CH2CH3)2 (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl2(1) (1a), Ir(η5-Cp*)Cl2(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl2(1) (1b), Ru(η6-p-cymene)Cl2(2) (2b) and copper(I) complexes: [Cu(CH3CN)2(1)BF4] (1c), [Cu(CH3CN)2(2)BF4] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC50 values significantly lower than that of the reference drug—cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type.

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“…On the other hand, EB penetrates the cells that had lost their membrane integrity, such as late apoptotic and dead cells, giving rise to orange fluorescence. [45,46] AO staining marked the early-stage apoptotic cells as yellow green granular nuclei. Late-stage apoptotic cells were characterized by orange fluorescence of EB staining (Figure 13).…”

Section: Probing the Mode Of Cell Death Through Staining Methodsmentioning

confidence: 99%

Impact of denticity of chromone/chromene thiosemicarbazones in the ruthenium(II)‐DMSO complexes on their cytotoxicity against breast cancer cells

Balakrishnan

Haribabu

Mahendiran

et al. 2022

Applied Organom Chemis

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Denticity plays a prominent role in the cytotoxicity of metal complexes. The impact of ligand denticity of chromone/chromene thiosemicarbazones (TSCs) in the Ru(II)-DMSO complexes on the cytotoxicity of cancer cells was evaluated. Ru(II)-DMSO complex containing tridentate chromone TSC (D1) exhibited better in vitro anticancer activity than the one with bidentate chromene TSC (D2). Using the optimized structures of the complexes, the reason behind the same was attributed to the thermodynamically stable nature of the tridentate system. Hydrolysis study of the complexes showed the kinetically labile nature of the chloride ligand in the tridentate species with respect to the bidentate counterpart. The selective cytotoxicity of complex D1 against breast cancer cells and its less toxicity against normal cells demonstrated the effective anticancer potential of the complex. Further, the binding efficacy of the complexes against DNA and BSA, along with imaging and flow cytometry experiments, warranted the effective cell death induced by the complexes against breast cancer cells via apoptosis.

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Impact of aliphatic acyl and aromatic thioamide substituents on the anticancer activity of Ru(ii)-p-cymene complexes with acylthiourea ligands—in vitro and in vivo studies

Abstract: Six different acylthiourea ligands (L1-L6) and their corresponding Ru(II)-p-cymene complexes (P1-P6) were designed to explore the structure-activity relationship of the complexes under the influence of aliphatic chain length and aromatic...

Cited by 71 publications

References 67 publications

Coordination Behavior of Acylthiourea Ligands in Their Ru(II)–Benzene Complexes─Structures and Anticancer Activity

Coordination Behavior of Acylthiourea Ligands in Their Ru(II)–Benzene Complexes─Structures and Anticancer Activity

Two out of Three Musketeers Fight against Cancer: Synthesis, Physicochemical, and Biological Properties of Phosphino CuI, RuII, IrIII Complexes

Impact of denticity of chromone/chromene thiosemicarbazones in the ruthenium(II)‐DMSO complexes on their cytotoxicity against breast cancer cells

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