Abstract
We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η6-Ph(CH2)3-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 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 2 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 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 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.
Highlights
The clinical anticancer drug cisplatin arose from the serendipitous discovery of its biological anticancer activity by Rosenberg et al about 50 years ago.[1]
The four neutral tethered RuII complexes [Ru(η6-Ph(CH2)3-ethylenediamine-N-R)Cl], where R = Ms (1), Ts (2), Tf (3), and Nb (4), were synthesized following a literature method for related complexes (Scheme 1). They were characterized by elemental analysis (CHN), highresolution mass spectrometry, and NMR (1H, 13C, and 19F) spectroscopy (Figures S1−S9 in the Supporting Information)
The η6-phenyl ring and ethylenediamine are linked by a three-carbon tether chain
Summary
The clinical anticancer drug cisplatin arose from the serendipitous discovery of its biological anticancer activity by Rosenberg et al about 50 years ago.[1]. Ruthenium complexes have shown promising potential with relatively low toxicity and might provide alternatives to platinum drugs. These Ru complexes have the potential to overcome the severe side effects and drug resistance which are problems with some platinum-based chemotherapeutics.[18,19] The two RuIII complexes NAMI-A and KP-1019 (Figure 1) have entered phase II clinical trials, the former as an antimetastatic agent.[20−22] The mode of action of NAMI-A and KP-1019 in cancer cells is not yet understood, but the reduction of RuIII to RuII is a plausible pathway for their activation.[23,24] The RuII complex [Ru(η6-p-cym)Cl2(PTA)]
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