Inhibition of Cancer Cell Growth by Ruthenium(II) Arene Complexes

Abstract

Inhibition of the growth of the human ovarian cancer cell line A2780 by organometallic ruthenium(II) complexes of the type [(eta(6)-arene)Ru(X)(Y)(Z)], where arene is benzene or substituted benzene, X, Y, and Z are halide, acetonitrile, or isonicotinamide, or X,Y is ethylenediamine (en) or N-ethylethylenediamine, has been investigated. The X-ray crystal structures of the complexes [(eta(6)-p-cymene)Ru(en)Cl]PF(6) (5), [(eta(6)-p-cymene)RuCl(2)(isonicotinamide)] (7), and [(eta(6)-biphenyl)Ru(en)Cl]PF(6) (9) are reported. They have "piano stool" geometries with eta(6) coordination of the arene ligand. Complexes with X,Y as a chelated en ligand and Z as a monofunctional leaving group had the highest activity. Complexes 5, 6 (the iodo analogue of 5), 9, and 10 (ethylethylenediamine analogue of 9) were as active as carboplatin. Hydrolysis of the reactive Ru-Cl bond in complex 5 was detected by HPLC but was suppressed by the addition of chloride ions. Complex 5 binds strongly and selectively to G bases on DNA oligonucleotides to form monofunctional adducts. No inhibition of topoisomerase I or II by complexes 5, 6, or 9 was detected. These chelated Ru(II) arene complexes have potential as novel metal-based anticancer agents with a mechanism of action different from that of the Ru(III) complex currently on clinical trial.

Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of highly cytotoxic anticancer agents

“…The dimers [(arene) 2 RuCl 2 ] 2 28 were prepared according to literature methods. Reactions were carried out under nitrogen.…”

“…To a Schlenk tube, the corresponding acid (5.2 mmol, 1.24 g for 1; 4.3 mmol, 1.01 g for 2; 5.2 mmol, 934 mg for 3; 4.3 mmol, 761 mg for 4), in the presence of the coupling reagents 4-(dimethylamino)pyridine (4 mmol, 492 mg for 1 and 3; 3.3 mmol, 401 mg for 2 and 4), N,N¢-dicyclohexylcarbodiimide (8 mmol, 1.66 g for 1 and 3; 6.6 mmol, 1.36 g for 2 and 4) and 4-pyrrolidinopyridine (4 mmol, 597 mg for 1 and 3; 3.3 mmol, 497 mg for 2 and 4) were dissolved in CH 2 Cl 2 (100 mL). After the addition of a solution of the diene (4 mmol, 500 mg for 1 and 3; 3.3 mmol, 500 mg for 2 and 4) in CH 2 Cl 2 (10 mL), the reaction was stirred at 20 • C during 18 h. Then resulting mixture was filtered through Celite and the solvent was removed under reduced pressure.…”

“…The dinuclear dichloro complex [(arene) 2 RuCl 2 ] 2 (0.15 mmol, 150 mg for 9, 162 mg for 10, 136 mg for 11, 144 mg for 12) was refluxed in technical grade EtOH (50 mL). As soon as the starting material was completely dissolved, a solution of thiophenol (0.9 mmol, 99 mg, 92 mL) in technical grade EtOH (5 mL) was added dropwise to the hot solution.…”

“…Water-soluble arene ruthenium complexes such as the prototype (p-i PrC 6 H 4 Me)Ru(P-pta)Cl 2 (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) (termed RAPTA-C) 1 and lipophilic compounds such as the benchmark [(C 6 H 5 Ph)Ru(N,Nen)Cl] + (en = 1,2-ethylenediamine) 2 have antitumoral or antimetastatic properties in vitro and in vivo. The anticancer potential of these types of compounds has been explained by their dual character, with the hydrogen bonding capacity of the pta or en ligands counterbalanced by the lipophilicity of the arene ligand, 3 while the mechanism of cytotoxic action is thought to involve hydrolysis of the Ru-Cl bond followed by reaction with the biomolecular target or targets.…”

“…The indane derivative undergoes aquation in the dark, and UV or visible light leads to a dissociation of the indane ligand and to the formation of strong diruthenium DNA adducts. 16 Based on our earlier work on dinuclear arene ruthenium complexes of the type [(arene) 2 3 ] + , which in the form of their chloride salts proved to be highly active against human ovarian cancer cell lines, with the cytotoxicity being in the submicromolar range. …”