Transfer Hydrogenation and Antiproliferative Activity of Tethered Half-Sandwich Organoruthenium Catalysts

Abstract

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η⁶-Ph(CH₂)₃-ethylenediamine-<i>N</i>-R)Cl], where R = methanesulfonyl (Ms, <b>1</b>), toluenesulfonyl (Ts, <b>2</b>), 4-trifluoromethylbenzenesulfonyl (Tf, <b>3</b>), and 4-nitrobenzenesulfonyl (Nb, <b>4</b>), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex <b>2</b> in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD⁺ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex <b>2</b> binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex <b>2</b> reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex <b>2</b> induced a dose-dependent G₁ cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity.