Ruthenium(II) arene PTA (RAPTA) complexes: impact of enantiomerically pure arene ligands

Shona Cammack, Catherine Marie Amélie Clavel, Paul Joseph Dyson, Kelly Joan Kilpin
Royal Society of Chemistry, 2013
Journal paper

Organometallic ruthenium(II) arene complexes containing the PTA ligand ([Ru(eta(6)-arene)Cl-2(PTA)], PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane, termed RAPTA) show pharmacologically relevant antitumour properties in vitro. Two new enantiomeric pairs of RAPTA compounds, containing the chiral arene (R)- or (S)-2-phenyl-N-(1-phenylethylene) acetamide and either dichlorido or oxalato ligands were synthesised and fully characterised. The stability of the complexes towards hydrolysis was assessed and the dichlorido complexes were found to be more stable towards hydrolysis than the prototype complex RAPTA-C, ([Ru(eta(6)-p-cymene) Cl-2(PTA)]). The cytotoxicity of the compounds towards human ovarian cancer cells is moderate to good with a degree of selectivity towards the cancer cells over healthy cells. More significantly, for the first time we were able to establish the influence of a bulky, chiral group attached to the arene on the cytotoxicity of this class of compound, with the S-enantiomer being more cytotoxic than the R-enantiomer.

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Shona Cammack, Catherine Marie Amélie Clavel, Paul Joseph Dyson, Kelly Joan Kilpin
Royal Society of Chemistry, 2013
Journal paper

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https://infoscience.epfl.ch/record/185207?ln=en

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Related publications

Selenoquinones Stabilized by Ruthenium( II) Arene Complexes: Synthesis, Structure, and Cytotoxicity

Catherine Marie Amélie Clavel, Paul Joseph Dyson

A new series of monoselenoquinone and diselenoquinone complexes, [((6)-p-cymene)Ru((4)-C6R4SeE)] (R=H, E=Se (6); R=CH3, E=Se (7); R=H, E=O (8)), as well as selenolate complexes [((6)-p-cymene)Ru((5)-C6H3R2Se)][SbF6] (R=H (9); R=CH3 (10)), stabilized by arene ruthenium moieties were prepared in good yields through nucleophilic substitution reactions from dichlorinated-arene and hydroxymonochlorinated-arene ruthenium complexes [((6)-p-cymene)Ru(C6R4XCl)]SbF6 (R=H, X=Cl (1); R=CH3, X=Cl (2); R=H, X=OH (3)) as well as the monochlorinated complexes [((6)-p-cymene)Ru((5)-C6H3R2Cl)]SbF6 (R=H (4); R=CH3 (5)). The X-ray crystallographic structures of two of the compounds, [((6)-p-cymene)Ru((4)-C6Me4Se2)] (7) and [((6)-p-cymene)Ru((4)-C6H4SeO)] (8), were determined. The structures confirm the identity of the target compounds and ascertain the coordination mode of these unprecedented ruthenium complexes of selenoquinones. Furthermore, these new compounds display relevant cytotoxic properties towards human ovarian cancer cells.

Wiley-V C H Verlag Gmbh2014

Combination of ruthenium(II)-arene complex [Ru(eta(6)-p-cymene)Cl-2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity

Ume-Gulsoom Abdul, Paul Joseph Dyson, Patrick Meraldi, Patrycja Nowak-Sliwinska

Ruthenium-based compounds show strong potential as anti-cancer drugs and are being investigated as alternatives to other well-established metal-based chemotherapeutics. The organometallic compound [Ru(eta(6)-p-cymene) Cl-2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C) exhibits broad acting anti-tumor efficacy with intrinsic angiostatic activity. In the search for an optimal anti-angiogenesis drug combination, we identified synergistic potential between RAPTA-C and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. This drug combination results in strong synergistic inhibition of cell viability in human endothelial (ECRF24 and HUVEC) and human ovarian carcinoma (A2780 and A2780cisR) cells. Additionally, erlotinib significantly enhances the cellular uptake of RAPTA-C relative to treatment with RAPTA-C alone in human ovarian carcinoma cells, but not endothelial cells. Drug combinations induce the formation of chromosome bridges that persist after mitotic exit and delay abscission in A2780 and A2780cisR, therefore suggesting initiation of cellular senescence. The therapeutic potential of these compounds and their combination is further validated in vivo on A2780 tumors grown on the chicken chorioallantoic membrane (CAM) model, and in a preclinical model in nude mice. Immunohistochemical analysis confirms effective anti-angiogenic and anti-proliferative activity in vivo, based on a significant reduction of microvascular density and a decrease in proliferating cells.

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Varying the metal to ethacrynic acid ratio in ruthenium(ii)/osmium(ii)-p-cymene conjugates

Catherine Marie Amélie Clavel, Paul Joseph Dyson, Emilia Paunescu, Mylène Soudani

Following the identification of a ruthenium(II)-arene complex with an ethacrynic acid-modified imidazole ligand, which inhibits glutathione transferase (GST) and is cytotoxic to chemo-resistant cancer cells, a series of structurally related ruthenium(II)- and osmium(II)-p-cymene compounds have been prepared. In these complexes the ethacrynic acid is linked to the metals via appropriately modified pyridine ligands. The influence of the metal center and the metal:ethacrynic acid ratio on the cytotoxicity of the compounds was evaluated with the derivatives with one metal center and two ethacrynic acid moieties being the most potent against chemo-resistant A2780cisR cells (human ovarian cancer cells with acquired resistance to cisplatin). Moreover, compared to a complex with an ethacrynic acid-modified imidazole ligand (RAIMID-EA, Figure 2), these complexes display a significant degree of cancer cell specificity.

Elsevier2017

Ruthenium

Ruthenium is a chemical element with the symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum grou

Enantiomer

In chemistry, an enantiomer (/ɪˈnænti.əmər, ɛ-, -oʊ-/ ih-NAN-tee-ə-mər; from Ancient Greek ἐνάντιος (enántios) 'opposite', and μέρος (méros) 'part') – also called optical isomer, antipode, or optica

Ovarian cancer

Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdome