Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand

Abstract

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) and [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) containing dichloroacetate(1–) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by 1H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC50 = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 μM for Ru-dca and IC50 = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes.

Dichloroacetate (DCA) and Cancer: An Overview towards Clinical Applications

“…Zirconium-based MOF loaded with DCA was also purposed as an attractive alternative to UiO-66, showing selective in vitro cytotoxicity towards several cancer cell lines and a good toleration by the immune system of several species [79]. Recently, Štarha et al [80] synthesized and characterized, for the first time, half-sandwich complexes containing ruthenium or osmium and DCA (Figure 2(a)). Both Ru-dca and Os-DCA complexes were screened in ovarian carcinoma cell lines, demonstrating to be more cytotoxic than cisplatin alone.…”

An anticancer Os(II) bathophenanthroline complex as a human breast cancer stem cell-selective, mammosphere potent agent that kills cells by necroptosis

“…Salinomycin, cisplatin, human serum albumin (HSA) and hEGF were from Sigma Aldrich (Darmstadt, Germany), B27 supplement, Dulbecco’s phosphate buffered saline (DPBS) and Corning CellStripper Dissociation Reagent (CSDR) from Thermo Fisher Scientific Inc. (MA, USA) and anti-CD44, anti-CD24 antibodies and isotype IgG controls from Miltenyi Biotec (Gladbach, Germany). Complexes [Ru( η 6 - p cym)(bphen)(dca)]PF 6 (complex 1 ) and [Os( η 6 - p cym)(bphen)(dca)]PF 6 (complex 2 ) ([ p cym = 1-methyl-4-(propan-2-yl)benzene ( p -cymene); bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] were prepared and characterized as described previously 9 . MCF-7 cells were kindly supplied by Professor B. Keppler, University of Vienna (Austria) and SKBR-3 cells were from the European collection of cell cultures (ECACC) (Salisbury, UK).…”

“…Recently, new half sandwich Ru(II) and Os(II) bathophenanthroline complexes [Ru( η 6 - p cym)(bphen)(dca)]PF 6 (Ru(II) complex 1 ) and [Os( η 6 - p cym)(bphen)(dca)]PF 6 (Os(II) complex 2 ) [ p cym = 1-methyl-4-(propan-2-yl)benzene ( p -cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] have been prepared and characterized 9 (Fig. 1).…”

Cytotoxic derivatives of dichloroacetic acid and some metal complexes

“…Two half-sandwich complexes of Ru (60a) and Os (60b) (Figure 23) containing a releasable DCA ligand have been reported to show good in vitro anticancer property against A2780 human ovarian carcinoma cells with IC 50 = 3.5 and 2.6 μM respectively, slightly higher than that of the clinically used platinum-based drug cisplatin (IC 50 = 5.9 μM). [96] However, they were much less toxic toward healthy human (SKBR-3 and MCF-7). [97] Importantly, 60b displayed remarkable submicromolar cytotoxicity for killing CSCs, which is considerably more efficient than that of its Ru analog 60a and salinomycin, known for one of the most selective CSC-targeting compounds.…”