The Contrasting Activity of Iodido versus Chlorido Ruthenium and Osmium Arene Azo- and Imino-pyridine Anticancer Complexes: Control of Cell Selectivity, Cross-Resistance, p53 Dependence, and Apoptosis Pathway

Abstract

activity of iodido versus chlorido ruthenium and osmium arene azo-and imino-pyridine anticancer complexes : control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway. Journal of Medicinal Chemistry, Vol.56 (No.3). pp. 1291-1300. Permanent WRAP url: http://wrap.warwick.ac.uk/53124 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes the work of researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-forprofit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. and X  Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not crossresistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in p53 mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor L-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d 6 metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. Publisher

Half-Sandwich Ru(II) Halogenido, Valproato and 4-Phenylbutyrato Complexes Containing 2,2′-Dipyridylamine: Synthesis, Characterization, Solution Chemistry and In Vitro Cytotoxicity

“…In this work, we decided to combine the above-described approaches, and study the effect of the replacement of the chlorido ligand with other halogenido ligands (a known approach utilized, for example, in the reference [3]) as well as by the VP and PB ligands (innovative approach in the field of Ru(II) anticancer complexes) on the in vitro cytotoxicity against the A2780 cells. For this purpose, we chose the easily-obtainable [Ru(η 6 -p-cym)(dpa)Cl]PF6 complex ( Figure 1) [10], recently reported as having moderate, and thus possibly tunable, in vitro cytotoxicity against the MCF-7 cancer cells (IC50 = 40.8 μM) [11].…”

“…In this work, the reaction time was considerably shortened to only 1 min, by using a microwave reactor. For the bromido (2) and iodido (3) complexes, instead of the known protocol starting from the appropriate dimeric compounds, [Ru(μ-Br)(η 6 -p-cym)Br]2 and [Ru(μ-I)(η 6 -p-cym)I]2 [17], the easily-obtainable chloride salt [Ru(η 6 -p-cym)(dpa)Cl]Cl (1*) was dechlorinated by 2 molar equivalents of silver triflate, followed by the addition of the appropriate potassium halogenide to form [Ru(η 6 -p-cym)(dpa)X] + (2,3). In the case of carboxylato complexes 4 and 5, a one-step replacement of the chlorido ligand of 1 by the VP or PB ones was achieved using the silver carboxylates Ag(VP) (for 4) or Ag(PB) (for 5).…”

“…Importantly, it has been reported that the decrease in the GSH level of cancer cells induced by (3). Non-hydrogen atoms are drawn as thermal ellipsoids at the 50% probability level.…”

“…Glutathione (GSH) is a naturally occurring tripeptide (Glu-Cys-Gly), known to be responsible for the intracellular detoxification of various transition metals [31], including ruthenium [32]. Importantly, it has been reported that the decrease in the GSH level of cancer cells induced by co-application of a γ-glutamylcysteine synthetase inhibitor, L-buthionine sulfoximine (L-BSO), led to the cytotoxicity enhancement for similar half-sandwich Ru(II) complexes [3], thus indicating the important role of GSH for cytotoxicity of prospective anticancer ruthenium complexes. That is why similar experiments, as described above, were performed for complexes 1-5 dissolved in 10% MeOD-d 4 /90% D 2 O, with an addition of 2 molar equivalents of GSH.…”

“…These complexes typically adopt a piano-stool geometry with η 6 -coordinated arene (e.g., p-cymene or benzene), chelating (XY) and monodentate (Z; typically chlorido ligand) ligands, together producing the compounds of the general composition [Ru II (η 6 -arene)(XY)Z] 0/+ . It has been reported that the in vitro cytotoxicity of these complexes can be improved when the chlorido ligand is replaced by different halogenido ligand, as exemplified on the [Ru(η 6 -p-cym)(L 1 )Cl]PF 6 and [Ru(η 6 -p-cym)(L 1 )I]PF 6 complexes, showing the IC 50 values of 16.2, and 3.0 µM, respectively, against the A2780 human ovarian carcinoma cells; L 1 = N,N-dimethyl-N -(2-pyridinylmethylene) [3].…”