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.
Highlights
Platinum(II) complexes cisplatin, carboplatin, and oxaliplatin represent the worldwide used metal-based anticancer chemotherapeutics [1]
The complexes were characterized by elemental analysis (C, H, N), electrospray ionization (ESI+) mass spectrometry, and 1H and 13C
For all the performed flow cytometry studies, the A2780 cells were pre-incubated in the 6-well plates
Summary
Platinum(II) complexes cisplatin, carboplatin, and oxaliplatin represent the worldwide used metal-based anticancer chemotherapeutics [1]. By adopting the same premise, that it research, it is quite surprising that to date only one work has been dealing with the studies of might becytotoxicity of great interest to investigate an impact of another type of simple bioactive carboxylate on of half-sandwich Ru(II) or Os(II) complex containing the monodentate releasable bioactive cytotoxicity non-platinum having in mindS-transferase the considerable ligandof(inhalf-sandwich particular deprotonated ethacrynic complexes, acid, a knownand inhibitor of glutathione anticancer effect [15], of above-mentioned we the chose dichloroacetate asbeaof suitable isoenzymes instead of the chloridomitaplatin one [16]. Sodium dichloroacetate is an approved drug for the of half-sandwich non-platinum complexes, and having in mind the considerable anticancer effect of treatment of lactic acidosis, with promising cytotoxic properties [17]. Ru-dca for Os-dca), given with theatom atom numbering numbering scheme
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