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

• Published in: Journal of inorganic biochemistry Vol. 175; pp. 198 - 207
• Main Authors: Păunescu, Emilia, Soudani, Mylène, Clavel, Catherine M., Dyson, Paul J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2017
• Subjects: Anticancer drugs; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bioorganometallic chemistry; Cell Line; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Ethacrynic acid; Ethacrynic Acid - chemistry; Ethacrynic Acid - pharmacology; Female; Glutathione Transferase - antagonists & inhibitors; Humans; Metal-based drugs; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Osmium - chemistry; Osmium - pharmacology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ruthenium - chemistry; Ruthenium - pharmacology; Metal-based drugs; Bioorganometallic chemistry; Anticancer drugs; Drug resistance; Ethacrynic acid
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2017.07.027

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. In a series of organometallic anticancer compounds conjugated to ethacrynic acid, a potent glutathione transferase inhibitor, the influence of the metal:ethacrynic acid ratio on cytotoxicity is assessed. [Display omitted] •New ethacrynic acid-modified ligands and associated organometallic complexes reported.•Influence of the metal (Ru vs Os) and the metal:ethacrynic acid ratio on cytotoxicity determined.•Metal:ethacrynic acid ratio 1:2 leads to the most active compounds.•Compounds are active against cisplatin-resistant human ovarian cancer cells.