Half-sandwich ruthenium(II)-arene complexes: synthesis, spectroscopic studies, biological properties, and molecular modeling

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (1H- and 13C-NMR, FT-IR), and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η6-arene)(XY)Cl](PF6) where arene = benzene or toluene and XY = bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic “piano-stool” configuration of Ru(II)-arene complexes—as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η6-p-cymene)(Me2dppz)Cl]PF6 complex (Me2dppz = 11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by molecular docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η6-benzene)(aip)Cl](PF6) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6, and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).This is the peer-reviewed version of the following article:Nikolić, S.; Grgurić-Šipka, S.; Djordjević, I. S.; Dahmani, R.; Dekanski, D.; Vidičević, S.; Tošić, J.; Mitić, D.; Grubišić, S. Half-Sandwich Ruthenium(II)-Arene Complexes: Synthesis, Spectroscopic Studies, Biological Properties, and Molecular Modeling. Journal of Coordination Chemistry 2019, 72 (1), 148–163. [https://doi.org/10.1080/00958972.2018.1553298].Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3753

Cytotoxic and cytoselective profile of novel ruthenium(II)-arene complexes with (fluoro substituated) picolinic acid

Background: Ruthenium containing compounds represent the most promising alternative to platinum-based chemotherapeutics whose therapeutic value has been limited by significant side effects. Advantageous features such as good aqueous solubility and relatively inert arene ligand make them very attractive for structural optimizations aimed for improved in vivo potency. Material and Methods: Reported complexes were obtained in a reaction of [Ru(η6-benzene)Cl(μ-Cl)]2 or [Ru(η6-toluene)Cl(μ-Cl)]2 with picolinic acid or 6-fluoropicolinic acid in a 1:2 molar ratio in ethanol and characterized by IR and NMR spectroscopy and MS spectrometry. Results: The cytotoxic profile was investigated by the colorimetric MTT assay, in a panel of human non-malignant cell line (MRC-5), and cancer cell lines (A549, HTB177, PC3, A375, HeLa, HCT116, MDA-MB-453). The complexes carrying picolinic acid, displayed moderate antiproliferative effect particularly toward colorectal carcinoma (HCT116) and cervix adenocarcinoma cells (HeLa). The highest activity and cytoselectivity was observed for complex with [Ru(η6-benzene)Cl(μ-Cl)]2 toward HCT116 cells: it was capable of reducing viability of HCT116 cells 1.5 times more efficiently (IC50 = 27.5 μM), than of the MRC-5 cells (IC50 = 41.3 μM). Conclusion: The complex with improved activity and selectivity is candidate for further investigations regarding its binding modes, sites, and affinities

Novel ruthenium complex K-2[Ru(dmgly)Cl-4] center dot 2H(2)O is toxic to C6 astrocytoma cell line, but not to primary rat astrocytes

A novel class of ruthenium (111) complexes of formulas K[Ru(sar)(2)Cl-2] - 1/2HO and K-2[Ru(dmgly)Cl-4] . 1/2H(2)O, containing biden2 tate chelates N-methylglycine (sarcosine, sar) or N,N-dimethylglycine (dnigly) and additional chloro ligands were synthesized. The complexes have been obtained by direct reaction of ruthenium(III) chloride with corresponding bidentate ligand followed by addition of base (KOH). These new complexes were characterized by elemental analysis, IR and electronic absorption spectroscopy. As astrocytomas, the most common of all brain tumors, are still very difficult to treat, we examined the influence of newly synthesized ruthenium-based complexes, as well as the earlier synthesized analogue platinum(IV) complexes [Pt(dmglY)(2)Cl-2], [Pt(sar)(2)Br-2] and [Pt(dmgly)(2)Br-2] on rat astrocytoma C6 cells in vitro. Among these complexes only K-2[Ru(dmglY)Cl-4].2H(2)O and [Pt(dMgIY)(2)Br-2] markedly inhibited the viability of non-confluent C6 cells. Furthermore, only complex K-2[Ru(dmgly)Cl4] .2H20 was able to reduce viability in confluent C6 cultures. Importantly, this complex was not toxic to primary rat astrocytes or macrophages. Having in mind that appropriate chemotherapy should be effective against tumor cells without harming normal tissues, complex K,[Ru(dmglY)Cl-4] - 2H(2)O could be a promising agent for developing therapeutics against astrocytomas. (C) 2004 Elsevier Inc. All rights reserved

In Sicilia sbarcati 800 migranti, altri seicento in arrivo. Ad Augusta i 24 morti dell'ultimo naufragio, repubblica.it, 27/08/2014

"I dispersi al largo della Libia sarebbero un centinaio. Tra i profughi approdati a Pozzallo c'era anche un gatto. Salvata una bimba di 14 mesi aggrappata a una tavola C'erano anche 81 donne e 133 minori tra i 449 migranti siriani, palestinesi ed egiziani arrivati a Pozzallo, nel ragusano, le cui operazioni di sbarco sono terminate intorno alle due della scorsa notte. Con il gruppo degli immigrati c'era anche un gatto, sottoposto poi a visita veterinaria per verificare che non fosse portatore..

[Pt(HPxSC)Cl-3], a novel platinum(IV) compound with anticancer properties

There has been a continuing effort for the discovery of novel platinum(IV)-based antitumor compounds with better therapeutic performances than cisplatin. In the present work, the anticancer action of recently synthesized Pt(IV)-based complex [Pt(HPxSC)Cl-3] was investigated using rat and human astrocytoma cell lines C6 and U251. [Pt(HPxSC)Cl-3] markedly reduced the number of cultured astrocytoma Cells (IC50, 80 mu M), as determined by crystal violet assay. The Pt(IV) complex induced apoptotic death of tumor cells, as flow cytometry analysis of the propidium iodide-stained cellular DNA revealed approx. 30% of hypodiploid cells in [Pt(HPxSC)Cl-3]-treated astrocytoma cell cultures. On the other hand, [Pt(HPxSC)Cl-3] at 200 mu M did not affect the viability of rat primary astrocytes, unlike the established anticancer drug cisplatin, which displayed high toxicity toward both astrocytoma cells (IC50, 15 mu M) and primary astrocytes (IC50, 20 mu M). Moreover, [Pt(HPxSC)Cl-3] at 100 mu M did not interfere with the ability of rat peritoneal macrophages to produce important antitumor molecules nitric oxide and tumor necrosis factor-a. Finally, we assessed the ability of [Pt(HPxSC)Cl-3] to restrain growth of some bacterial and yeast strains, but it showed rather limited antimicrobial activity. (c) 2005 Elsevier B.V. All rights reserved

Synthesis and in vitro Anticancer Activity of Ruthenium-Cymene Complexes with Cyclohexyl-Functionalized Ethylenediamine-N,N '-diacetate-Type Ligands

Herein we describe the synthesis, characterization, and anticancer activity of novel p-cymeneruthenium(II) complexes containing methyl, ethyl, n-propyl, and n-butyl esters of (S, S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, (1)H, and (13)C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL-60, K562, and REH cells (IC(50) : 1.0-20.2 mu m), with the n-butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n-butyl ester complex is more effective against leukemic patients' blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of Ru(II)-based compounds

Synthesis and in vitro Anticancer Activity of Ruthenium-Cymene Complexes with Cyclohexyl-Functionalized Ethylenediamine-N,N '-diacetate-Type Ligands

Herein we describe the synthesis, characterization, and anticancer activity of novel p-cymeneruthenium(II) complexes containing methyl, ethyl, n-propyl, and n-butyl esters of (S, S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, (1)H, and (13)C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL-60, K562, and REH cells (IC(50) : 1.0-20.2 mu m), with the n-butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n-butyl ester complex is more effective against leukemic patients' blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of Ru(II)-based compounds

Cyclohexyl Analogues of Ethylenediamine Dipropanoic Acid Induce Caspase-Independent Mitochondrial Apoptosis in Human Leukemic Cells

We investigated the cytotoxicity of recently synthesized (S,S)-ethyleridiamine-N,N'-di-2-(3-cyclohexyl)propanoic acid esters toward human leukemic cell lines and healthy blood mononuclear cells. Cell viability was assessed by acid phosphatase assay, apoptosis, and differentiation were analyzed by flow cytometry and electron microscopy, while intracellular localization of apoptosis-inducing factor (AIF) was determined by immunoblotting. It was demonstrated that methyl, ethyl, and n-propyl esters were toxic to HL-60, REH, MOLT-4, KG-1, JVM-2, and K-562 leukemic cell lines, while the nonesterified parental compound and n-butyl ester were devoid of cytotoxic action. The ethyl ester exhibited the highest cytotoxic activity (IC50 10.7 mu M-45.4 mu M), which was comparable to that of the prototypical anticancer drug cisplatin. The observed cytotoxic effect in HL-60 cells was associated with an increase in superoxide production and mitochondrial membrane depolarization, leading to apoptotic cell death characterized by phosphatidylserine externalization and DNA fragmentation in the absence of autophagic response. DNA fragmentation preceded caspase activation and followed AIF translocation from mitochondria to nucleus, which was indicative of caspase-independent apoptotic cell death. HL-60 cells treated with subtoxic concentration of the compound displayed morphological signs of granulocytic differentiation (nuclear indentations and presence of cytoplasmic primary granules), as well as an increased expression of differentiation markers CD11b and CD15. The cyclohexyl analogues of ethylenediamine dipropanoic acid were also toxic to peripheral blood mononuclear cells of both healthy controls and leukemic patients, the latter being more sensitive. Our data demonstrate that the toxicity of the investigated cyclohexyl compounds against leukemic cell lines is mediated by caspase-independent apoptosis associated with oxidative stress, mitochondrial dysfunction, and AIF translocation