Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms

Abstract

(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity.

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues

“…All β-hydroxydithiocinnamic acid esters L1–L6 were synthesized and characterized as described previously [ 18 , 50 ]. Ligands L1–L6 were diluted in 15 mL acetonitrile in a flask and deprotonated with sodium acetate, and the corresponding metal salt was added.…”

“…Interesting changes are observable for the methine proton, signal 1. Whereas Ni2, Pd2, Pt2, and PtDMSO2 show a shift to higher ppm values compared to L2, the opposite is shown for Ru2 and Os2 [ 18 , 50 ]. This is potentially caused by the better donor ability of the cymene ligand.…”

“…The toxic influence of DMSO was determined earlier, and experiments were carried out with 0.5 % DMSO in cell culture media and used as a reference in MTT assays (see Section 3 ) [ 18 ]. The conditions of these experiments were the same as for PtDMSO, Ru(II), and Os(II), and have been published [ 18 , 49 , 50 ]. Thus, alongside comparisons of different metals and different substitution patterns of the ligands described in this paper, comparisons to the other already published systems are possible.…”

“…Thus, alongside comparisons of different metals and different substitution patterns of the ligands described in this paper, comparisons to the other already published systems are possible. Additionally, the IC 50 values of the different β-hydroxydithiocinnamic acid ester ligands have previously been evaluated [ 50 ].…”

“…Recently, a novel mixed platinum(II) complex with an O , S -chelating ligand and the general formula [Pt(PPh 3 ) 2 (L- O , S )]PF 6 (L- O , S = N , N -morpholine- N ′-benzoylthiourea) has been synthetized and tested, and proves to be active against tumor cells. The choice of the β-hydroxydithiocinnamic acid ester as the ligand system is based on our described promising results for ruthenium(II) and osmium(II) complexes also bearing this O , S -bidendate ligand [ 49 , 50 ].…”