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A potential method to improve the in vitro cytotoxicity of half-sandwich Os(II) complexes against A2780 cells

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Abstract

The [Os(η6-pcym)(dpa)(VP)]PF6 (1-VP) complex contains the histone deacetylase (HDAC) inhibitor valproate (2-propylpentanoate; VP) as a monodentate O-donor ligand and shows ca. 3-fold higher in vitro cytotoxicity against A2780 human ovarian carcinoma cells than its chlorido analogue [Os(η6-pcym)(dpa)Cl]PF6 (1-Cl); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), dpa = 2,2′-dipyridylamine. The complex 1-VP showed promising selectivity towards the A2780 ovarian carcinoma cell line (IC50 = 20.9 μM) over normal human hepatocytes (IC50 > 200.0 μM). Moreover, the complex 1-VP was found to be inactive against MCF-7 (breast adenocarcinoma), PANC-1 (pancreatic adenocarcinoma) and HT-29 (colon carcinoma) up to a concentration of 100 μM. Detailed flow cytometry studies indicated that treatment of A2780 cells with complex 1-VP led to induction of apoptosis, production of reactive oxygen species (ROS) and superoxide (SO) anion radicals, as well as mitochondrial membrane potential depletion and cell cycle perturbations. The microscopic assessment (standard hematoxylin/eosin staining) revealed signs of morphological changes associated with the progression of apoptosis in A2780 cells treated with the IC50 concentration of the complex 1-VP. Consistent with the intracellular production of ROS and SO, the complex 1-VP induced hydroxyl radical formation, as proved by EPR spin trapping experiments. This case study suggests that replacement of the chlorido ligand of half-sandwich Os(II) complexes by a releasable monodentate biologically active ligand (e.g., VP used in this study) is an effective strategy for the development of novel non-platinum cytotoxic agents.

Graphical abstract: A potential method to improve the in vitro cytotoxicity of half-sandwich Os(ii) complexes against A2780 cells

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Publication details

The article was received on 16 Jan 2018, accepted on 20 Mar 2018 and first published on 21 Mar 2018


Article type: Paper
DOI: 10.1039/C8DT00193F
Citation: Dalton Trans., 2018, Advance Article
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    A potential method to improve the in vitro cytotoxicity of half-sandwich Os(II) complexes against A2780 cells

    P. Štarha, Z. Trávníček, R. Herchel, P. Jewula and Z. Dvořák, Dalton Trans., 2018, Advance Article , DOI: 10.1039/C8DT00193F

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