New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

• Published in: Inorganic chemistry 2013-08, Vol.52 (15), p.9039-9052
• Main Authors: Kljun, Jakob, Bratsos, Ioannis, Alessio, Enzo, Psomas, George, Repnik, Urška, Butinar, Miha, Turk, Boris, Turel, Iztok
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Cathepsins - antagonists & inhibitors; DNA - metabolism; Ethidium - metabolism; HeLa Cells; Humans; Models, Molecular; Molecular Conformation; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Quinolones - chemistry; Ruthenium - chemistry; Serum Albumin, Bovine - metabolism; Water - chemistry
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic401220x

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ 2 O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV–vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes 1–4. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound 4, which also shows the most pronounced rate of hydrolysis. Compounds 2 and 4 also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex 2 displayed moderate cytotoxicity when tested on the HeLa cell line.