Ruthenium Anticancer Compounds with Biologically‐derived Ligands

Mu, Changhua; Walsby, Charles J.

doi:10.1002/9781118697191.ch15

Cited by 7 publications

(6 citation statements)

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“…NAMI-A is active against tumor metastases [ 13 ], whereas KP1019 and NKP-1339 directly cause apoptotic cell death through the intrinsic mitochondrial pathway and the formation of reactive oxygen species [ 17 , 20 ]. Furthermore, the cytotoxicity of many ruthenium(III) prodrugs has been linked to the reduction of Ru(III) to Ru(II) species in vivo [ 20 , 21 ], although the role this plays in the activity of the complexes remains controversial [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Ruthenium(II)/(III) DMSO-Based Complexes of 2-Aminophenyl Benzimidazole with In Vitro and In Vivo Anticancer Activity

et al. 2020

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New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects.

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Section: Introductionmentioning

confidence: 99%

Ruthenium(II)/(III) DMSO-Based Complexes of 2-Aminophenyl Benzimidazole with In Vitro and In Vivo Anticancer Activity

et al. 2020

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“…While these types of octahedral Ru(III) coordination complexes continue to undergo development, organometallic Ru-arene complexes are becoming increasingly predominant in the ruthenium anticancer literature . Ru piano-stool complexes like those shown in Figure are a particular focus of progress in this area, and numerous derivatives of these compounds have been described …”

Section: Introductionmentioning

confidence: 99%

Activation by Oxidation: Ferrocene-Functionalized Ru(II)-Arene Complexes with Anticancer, Antibacterial, and Antioxidant Properties

Prosser

Harrypersad

et al. 2018

Inorg. Chem.

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Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal MIII/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC50 values correlated quantitatively with the Fc+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC50 values indicate that linking of the Ru and Fc centers promotes antioxidant activity.

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“…1 H-NOESY-1D spectra were recorded with a 500 Bruker Ascend instrument operating at room temperature (500 MHz for 1 H) relative to TMS. 31 P NMR spectra were recorded with a 400 Mercury Plus Varian instrument operating at room temperature, 162 MHz relative to 85% H 3 PO 4 . Positive and negative ion electrospray ionization mass spectra (ESI-MS) were obtained on a Series 1100 MSI detector HP spectrometer using methanol as the mobile phase.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…However, these compounds pose some major drawbacks such as high general toxicity and limited activity in certain cancers, leading to drug-development programs aimed at overcoming these disadvantages. − In one such approach based on constructing drugs from metals other than platinum, ruthenium-based anticancer compounds have been found to show promising anticancer properties. In particular, Ru(II)–arene complexes with the half-sandwich (also known as “piano-stool”) structure have gained increasing interest in recent years due to favorable in vivo data. − Indeed, Ru(II)–arene complexes possess remarkable features that make them well suited as antitumor agents that typically involve very different biomolecular targets to platinum-based compounds. − The half-sandwich piano-stool structure has recently been explored also for the neighboring metals of group 9, i.e., rhodium and iridium, which have been less investigated as metallodrugs. − Piano-stool pentamethylcyclopentadienyl (Cp*) Rh(III) and Ir(III) complexes possess relevant cytotoxicities against cancer cells, − and in some cases they exhibit a superior activity to that of related Ru(II)–arene complexes. , The anticancer activity of these compounds can be enhanced using chelating ligands of natural or synthetic origin, which possess complementary biological activity. − In this respect, O,O′-chelating β-diketones are useful scaffolds in the synthesis of organometallic complexes with biological activity . Dibenzoylmethane (DBMH, Scheme ), a naturally occurring β-diketone, is a minor constituent of liquorice roots ( Glycyrrhiza glabra of the family Leguminosae), which has been identified as a promising antimutagenic and anticarcinogenic compound. , A synthetic derivative of dibenzoylmethane that is characterized by the presence of a hydroxyl group bound to one of the aromatic rings, namely o -hydroxydibenzoylmethane (HDBH, Scheme ), inhibits cell proliferation more efficiently than dibenzoylmethane, and it is also able to induce apoptosis in carcinoma and adenocarcinoma cell lines. − Avobenzone (AVBH, ...…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic Half-Sandwich Rh(III) and Ir(III) β-Diketonates

Petrini¹,

Pettinari²,

Marchetti³

et al. 2017

Inorg. Chem.

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A series of half-sandwich pentamethylcyclopentadienyl rhodium(III) and iridium(III) complexes [Cp*M(DBM/HDB/AVB)Cl] and [Cp*M(DBM/HDB/AVB)(PTA)][SOCF], where Cp* = pentamethylcyclopentadienyl, the proligands DBMH = dibenzoylmethane, HDBH = o-hydroxydibenzoylmethane, AVBH = avobenzone, and PTA = 1,3,5-triaza-7-phosphaadamantane, is reported. All the complexes were characterized by IR, H andC NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and DFT calculations. Five of the complexes have also been characterized in the solid-state by X-ray crystallography. The cytotoxicity of the complexes has been evaluated against human ovarian A2780 and A2780cisR cell lines and, with the only exception of complexes 1 and 2 that display a negligible cytotoxicity, exhibit moderate cytotoxicity toward both cancer cell lines. However, the complexes do not show cancer cell selectivity with respect to human embryonic kidney HEK293 cells.

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Ruthenium Anticancer Compounds with Biologically‐derived Ligands

Cited by 7 publications

References 233 publications

Ruthenium(II)/(III) DMSO-Based Complexes of 2-Aminophenyl Benzimidazole with In Vitro and In Vivo Anticancer Activity

Ruthenium(II)/(III) DMSO-Based Complexes of 2-Aminophenyl Benzimidazole with In Vitro and In Vivo Anticancer Activity

Activation by Oxidation: Ferrocene-Functionalized Ru(II)-Arene Complexes with Anticancer, Antibacterial, and Antioxidant Properties

Cytotoxic Half-Sandwich Rh(III) and Ir(III) β-Diketonates

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