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Three new ruthenium(II) complexes were synthesized from different substituted isothiazole ligands 5-(methylamino)-3-pyrrolidine-1-ylisothiazole-4-carbonitrile (1), 5-(methylamino)-3-(4-methylpiperazine-1-yl)isothiazole-4-carbonitrile (2) and 5-(methylamino)-3-morpholine-4-ylisothiazole-4-carbonitrile (3): [Ru(η⁶-p-cymene)Cl₂(L1)]·H₂O (4), [Ru(η⁶-p-cymene)Cl₂(L2)] (5) and [Ru(η⁶-p-cymene)Cl₂(L3)] (6). All complexes were characterized by IR, UV-Vis, NMR spectroscopy, and elemental analysis. The molecular structures of all ligands and complexes 4 and 6 were determined by an X-ray. The results of the interactions of CT-DNA (calf thymus deoxyribonucleic acid) and HSA (human serum albumin) with ruthenium (II) complexes reveal that complex 4 binds well to CT-DNA and HSA. Kinetic and thermodynamic parameters for the reaction between complex and HSA confirmed the associative mode of interaction. The results of Quantum mechanics (QM) modelling and docking experiments toward DNA dodecamer and HSA support the strongest binding of the complex 4 to DNA major groove, as well as its binding to IIa domain of HSA with the lowest ΔG energy, which agrees with the solution studies. The modified GOLD docking results are indicative for Ru(p-cymene)LCl··(HSA··GLU292) binding and GOLD/MOPAC(QM) docking/modelling of DNA/Ligand (Ru(II)-N(7)dG7) covalent binding. The cytotoxic activity of compounds was evaluated by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Neither of the tested compounds shows activity against a healthy MRC-5 cell line while the MCF-7 cell line is the most sensitive to all. Compounds 3, 4 and 5 were about two times more active than cisplatin, while the antiproliferative activity of 6 was almost the same as with cisplatin. Flow cytometry analysis showed the apoptotic death of the cells with a cell cycle arrest in the subG1 phase. Show less

Herein the design and synthesis of a new 8-hydroxyquinoline derivative, (S)-5-chloro-7-((proline-1-yl)methyl)8-hydroxyquinoline (HQCl-Pro), with good water solubility and multidrug resistance reversal activity are reported. In this work the proton dissociation processes of HQCl-Pro and its complex formation with [Rh(η⁵-C₅Me₅)(H₂O)₃]²⁺, [Ru(η⁶-p-cymene)(H₂O)₃]²⁺ and [Ru(η⁶-toluene)(H₂O)₃]²⁺ were investigated by the combined use of pH-potentiometry, UV-visible spectrometry and ¹H NMR spectroscopy. Our results revealed the prominent solution stability of the complexes in all cases. The lipophilicity of the complexes increased with the chloride ion concentration, and the complexes showed moderate log D values (-0.8 to +0.4) at pH 7.4 at all tested Cl^- concentrations. The formation of mixed hydroxido complexes from the aqua complexes was characterized by relatively high pK_a values (8.45-9.62 in chloride-free medium). Complexation processes are much slower with the Ru(η⁶-arene) triaqua cations than with [Rh(η⁵-C₅Me₅)(H₂O)₃]²⁺. Both the pK_a values and H₂O/Cl^- exchange constants of the Ru-complexes are lower by 0.5-1.0 orders of magnitude than those of the Rh analogue. Arene loss (p-cymene and toluene) and oxidation were found in the case of Ru-complexes when an excess of HQCl-Pro and aromatic (N,N) bidentate ligands was added. The cytotoxicity and antiproliferative effect of HQCl-Pro and its complexes were assayed in vitro. In contrast to the structurally familiar 8-hydroxyquinoline, HQCl-Pro and its Rh(η⁵-C₅Me₅) complex were somewhat more effective against drug resistant Colo 320 adenocarcinoma human cells compared to the drug sensitive Colo 205 cells. The Ru- and Rh-complexes showed a similar metal uptake level after 4 h, while a longer incubation time resulted in higher cellular Rh concentration. Show less

Six new ruthenium(ii) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P-P)(bipy)]PF6, where L = Lap or Law, P-P = 1,2'-bis(diphenylphosphino)ethane (dppe), 1,4'-bis(diphenylphosphino)butane (dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2'-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cisplatin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the "normal-like" human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents. Show less

Subtle ligand modifications on Ru^II -polypyridyl complexes may result in different excited-state characteristics, which provides the opportunity to tune their photo-physicochemical properties and subsequently change their biological functions. Here, a DNA-targeting Ru^II -polypyridyl complex (named Ru1) with highly photosensitizing ³ IL (intraligand) excited state was designed based on a classical DNA-intercalator [Ru(bpy)₂ (dppz)]⋅2 PF₆ by incorporation of the dppz (dipyrido[3,2-a:2',3'-c]phenazine) ligand tethered with a pyrenyl group, which has four orders of magnitude higher potency than the model complex [Ru(bpy)₂ (dppz)]⋅2 PF₆ upon light irradiation. This study provides a facile strategy for the design of organelle-targeting Ru^II -polypyridyl complexes with dramatically improved photobiological activity. Show less

Organometallic Ru(II)-arene complexes have emerged as potential alternatives to platinum appended agents due to their wide range of interesting features such as stability in solution and solid, significant activity, less toxicity and hydrophobic property of arene moiety, etc. Hence, a series of Ru(II)-p-cymene complexes, [(η⁶-p-cymene)Ru(η²-N,N-L1)Cl]Cl (1), [(η⁶-p-cymene)Ru(η¹-N-L2)Cl₂] (2) and [(η⁶-p-cymene)Ru(η¹-N-L3)Cl₂] (3) were prepared from pyrazole based ligands [2-(1H-pyrazol-3-yl)pyridine (L1), 3-(furan-2-yl)-1H-pyrazole (L2) and 3-(thiophen-2-yl)-1H-pyrazole (L3)], and [RuCl₂-(η⁶-p-cymene)] dimer. The new Ru(II)-p-cymene complexes were well characterized by elemental analysis, and spectroscopic (FT-IR, UV-Visible, ¹H NMR, ¹³C NMR and mass) and crystallographic methods. The Ru(II)-p-cymene complexes (1-3) were found to adopt their characteristic piano stool geometry around Ru(II) ion. The calf thymus DNA (CT-DNA) binding ability of the new complexes was investigated by electronic absorption spectroscopic titration and viscosity methods. The molecular docking study results showed that complex 1 strongly bound with targeted biomolecules than 2 and 3. Docked poses of bidentate pyrazole based Ru(II)-p-cymene complex 1 revealed that the complex formed a crucial guanine N⁷ position hydrogen bond with DNA receptor. Complexes 1-3 might hydrolyze under physiological conditions and form aqua complexes 4-8, and docking calculations showed that the aqua complexes bound strongly with the receptors than original complexes. The in vitro cytotoxicity of the Ru(II)-p-cymene complexes and cisplatin was evaluated against triple negative breast cancer (TNBC) MDA-MB-231 cells. Our results showed that the inhibitory effect of bidentate pyrazole based Ru(II)-p-cymene complex 1 on the growth of breast cancer cells was superior to other tested complexes. Show less

We herein report the synthesis, characterization and anticancer activity of BTPIP (2-(4-(benzo[b]thiophen-2-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(NN)₂(BTPIP)](ClO₄)₂ (N-N = bpy = 2,2'-bipyridine, Ru(II)-1; phen = 1,10-phenanthroline, Ru(II)-2; dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3; dmp = 2,9-dimethyl-1,10-phenanthroline, Ru(II)-4). The DNA binding behaviors reveal that the complexes bind to calf thymus DNA by intercalation. Cytotoxicity of the complexes against A549, HepG-2, SGC-7901 and Hela cells were evaluated in vitro. Complexes Ru(II)-1, Ru(II)-2, Ru(II)-3, Ru(II)-4 show moderate activity on the cell proliferation in A549 cells with IC₅₀ values of 9.3 ± 1.2, 12.1 ± 1.6, 10.3 ± 1.6, 8.9 ± 1.2 μM, respectively. Apoptosis assessment, intracellular mitochondrial membrane potential (MMP), location in mitochondria, reactive oxygen species (ROS), cell invasion assay and cell cycle arrest were also performed to explore the mechanism of this action. When the concentration of the ruthenium(II) complexes is increased, the amount of reactive oxygen species increases obviously and the mitochondrial membrane potential decreases dramatically in A549 cells. Most importantly, the ruthenium(II) polypyridyl complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. These results showed that the ruthenium(II) complexes could induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway. Show less

Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)₂smp](PF₆) (1) and [Ru(phen)₂smp](PF₆) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115. Show less

In this work, five naphthalimide-modified half-sandwich iridium and ruthenium complexes ([(η⁵-Cp^x)Ir(NˆN)Cl]PF₆, [(η⁶-p-cym)Ru(NˆN)Cl]PF₆) have been presented. The anticancer activities of the complexes against various cancer cell lines were investigated, among them, complexes 2 and 4 showed better anticancer activity than cisplatin, and their anticancer activity is better than complex 5 without fluorophore. In addition, a series of biological tests of complex 2 were performed using flow cytometry, the results indicated that the complex could induce cell death in a variety of ways. By changing of the ligands, the complexes exhibited different photophysical properties, and the mechanism of action of the complexes entering the cell and inducing apoptosis are different. Moreover, complex 2 successfully targeted mitochondria, while complex 4 targeted lysosomes, causing mitochondrial damage and lysosomal damage to induce apoptosis. Excitingly, complex 2 has good antimetastatic ability to cancer cells. Furthermore, complexes 2 and 4 did not have a significant effect on the NADH binding reaction, but they had a moderate binding ability to BSA. Show less

Eight new organometallic Ru(II)-arene complexes of the type [RuCl₂(η⁶-arene)(η¹-S-aroylthiourea)] (arene = p-cymene or benzene) were synthesized in order to evaluate the effect of the arene moiety and the substituent of the aroylthiourea ligand on the cytotoxicity of the complexes. The ligands (L1 and L2) and complexes (1-8) were characterized using analytical and spectroscopic (UV-visible, infrared, ¹H NMR, ¹³C NMR, and mass) methods. The structure of the ligands (L1 and L2) and complexes (1 and 3-6) was obtained from single-crystal X-ray diffraction studies. The cytotoxicity of the complexes was evaluated against four different cancer cell lines: MCF-7 (breast), COLO 205 (colon), A549 (lung), and IMR-32 (neuroblastoma). All the complexes showed good cytotoxicity and the highest was in the IMR-32 cell line, which articulates the specificity of these complexes toward the IMR-32 cancer cell line. The complexes 5, 7, and 8 exhibited remarkable cytotoxicity in the entire cancer cell lines tested, which was comparable with the standard drug, cisplatin. The anticancer mechanism of the complexes 3 and 7 in IMR-32 cells was evaluated by bright-field microscopy, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), DNA damage, and caspase-3 analyses. The cells treated with the complexes showed upregulated caspase-3 compared to the control, and it was found that ROS and MMP were dose-dependent on analysis. Also, bright-field microscopy and 4',6-diamidino-2-phenylindole (DAPI) staining have correspondingly shown cellular membrane blebbing and DNA damage, which were morphological hallmarks of apoptosis. The study concluded that the complexes promoted the oxidative stress-mediated apoptotic death of the cancer cells through the generation of intracellular ROS, depletion of MMP, and damage of the nuclear material. Show less

Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η⁶ -p-cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono- or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4-membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays. Show less

A novel ligand BOPIP (BOPIP = {2-(4-(benzyloxy)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline}) and its mononuclear Ru(II) polypyridyl complexes [Ru(phen)₂ BOPIP]²⁺(1) (phen = 1,10-Phenanthrolene), [Ru(bpy)₂ BOPIP]²⁺(2) (bpy = 2,2' bipyridyl), [Ru(dmb)₂ BOPIP]²⁺(3) (dmb = 4, 4' -dimethyl 2, 2' -bipyridine), [Ru(Hdpa)₂ BOPIP]²⁺(4) (Hdpa = 2,2'dipyridylamine) have been synthesized successfully and characterized by elemental analysis, UV-vis, IR, ¹H, ¹³ C-NMR, and ESI-MS Spectroscopy. The interaction of these complexes with CT-DNA was studied using absorption, emission techniques, viscosity measurements and molecular docking studies. The docking study also supports the binding ability of complexes obtained through the absorption and emission techniques. These studies reveal that the Four Ru(II) polypyridyl complexes bind to DNA predominantly by intercalation. The Antimicrobial activity and cytotoxicity of these complexes are also reported. Show less

A series of nanomaterials based on mesoporous silica have been synthesised and functionalised with a photoactive polypyridyl ruthenium(ii) complex, namely [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), by various methods. The functionalisation reactions were based on the covalent binding to different ligands attached to the pores of the mesoporous nanoparticles and a simple physisorption using polyamino-functionalised mesoporous silica nanoparticles. The resulting nanostructured systems have been characterised by XRD, XRF, BET, SEM and TEM, observing the incorporation of the metallodrug onto the nanostructured silica in a different way depending on the synthetic method used in the loading reactions. In our studies, we have also observed that functionalisation with the metallodrug causes changes in the structural and textural features of the materials. The phototherapeutic activity of the ruthenium-functionalised materials in HeLa cervical cancer cells has been tested and the preliminary results are presented herein. Show less

Three new ruthenium(II)-arene complexes with pyrido[2',3':5,6]pyrazino[2,3-f][1, 10]phenanthroline (ppf) of general formula: C1 ([(ƞ⁶-benzene)Ru(ppf)Cl]PF₆, C2 ([(ƞ⁶-toluene)Ru(ppf)Cl]PF₆) and C3 ([(ƞ⁶-p-cymene)Ru(ppf)Cl]PF₆) have been synthesized. The structures of complexes were determined by elemental analysis, IR, ESI-MS, as well as with ¹H and ¹³C NMR spectroscopy. Cytotoxic activity has been evaluated in three different human neoplastic cell lines (A549, A375, LS 174T) and in one human non-tumor cell line (MRC-5), by the MTT assay. Complexes C1-C3 showed IC₅₀ values in the micromolar range below 100 µM. Complex C3, carrying ƞ⁶-p-cymene as the arene ligand, exhibited cytoselective activity toward human malignant melanoma A375 cells (IC₅₀ = 15.8 ± 2.7 µM), and has been selected for further analyses of its biological effects. Drug-accumulation study performed in the A375 cells disclosed that C3 possess lower ability of entering the cells compared to cisplatin and distributes approximately equally in the cytosol and membrane/organelle fraction of cells. Investigations in the 3D model of A375 cells, disclosed different effects of the complex C3 and cisplatin on growth of multicellular tumor spheroids (MCTSs). While the size of cisplatin-treated MCTSs decreased with time, MCTSs treated with C3 continued to growth. Differences in structural organization and biological activity of this type of ruthenium(II)-arene complexes versus cisplatin in A375 malignant melanoma cells pointed out their different modes of action, and necessity for further biological studies and optimizations for potential applications. Show less

Organoruthenium complexes are potent alternatives for platinum-based complexes because of their superior anticancer activity. In this investigation, a series of new Ru(II)-arene complexes with triarylamine-thiosemicarbazone hybrid ligands with higher anticancer activity than cisplatin are reported. The molecular structure of the ligands and complexes was confirmed spectroscopically and supported by single-crystal X-ray crystallography. These complexes adopted a three-leg piano stool geometry. All the Ru(II)-arene complexes were systematically investigated for their in vitro cytotoxicity against human cervical (HeLa S3), lung (A549) cancer, and human normal lung (IMR-90) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Interestingly, a pyrrolidine-attached Ru(II)-benzene complex exhibited superior activity against cancer cells with low IC₅₀ values, and colony formation study showed complete inhibition at 5 and 10 μM concentration. Furthermore, morphological changes assessed by acridine orange and propidium iodide staining revealed that the cell death occurred by apoptosis. In addition, the interaction between synthesized Ru(II)-arene complexes and DNA/protein was explored by absorption and emission spectroscopy methods. These synthesized new organoruthenium complexes can be used for developing new metal-based anticancer drugs. Show less

Most half-sandwich metal anticancer complexes are non-fluorescent, which results in an uncertain mechanism of action (MoA). We designed and synthesized eight fluorescent half-sandwich iridium (Ir) and ruthenium (Ru) complexes by introducing rhodamine derivatives into the N^N-chelating ligand. These complexes have features of bio-imaging and anticancer agents and may merit future development as novel anticancer agents. Show less

The monocationic chloro complexes containing chelating N∩N ligands: [(η⁶-p-cymene)Ru(L1-4)Cl]⁺ (1-4), where L1 = 4-methyl-1,10-phenantroline, L2 = dipyrido[3,2-a:2',3'-c]phenazine, L3 = 11-chloro-dipyrido[3,2-a:2',3'-c]phenazine, L4 = 11-nitro-dipyrido[3,2-a:2',3'-c]phenazine; p-cymene = 1-methyl-4-isopropylbenzene) have been prepared and characterized as the hexafluorophosphate salts. The biological activity of 1-4 has been investigated in selected 2D monolayer cell cultures (A549, PANC-1, MDA-MB-231, MRC-5). All investigated ruthenium complexes showed similar or even better cytotoxicity to cisplatin. However, there was no significant reduction in growth of PANC-1 cells in a 3D cell culture of multicellular tumor spheroids (MCTS) after treatment with 2-4, while the cisplatin treatment induced retardation in MCTS growth. Flow cytometry analysis of the cell cycle of PANC-1 cells shows that 3 caused changes of cell cycle phase distribution characterized by slight accumulation of cells in the G2-M phase. Absence of the Sub-G1 phase in the cell cycle of the treated cells indicated that there was no fragmentation of DNA for the analyzed time intervals (48 and 72 h treatment). Fluorescent microscopy, after acridine orange/ethidium bromide staining, revealed that the investigated ruthenium complexes induced some characteristics of apoptotic morphology (shrinking and condensation of chromatin) with notably preserved integrity of the plasma membrane. Investigation of cellular uptake and DNA - fraction accumulation performed by inductively coupled plasma mass spectrometry in PANC-1 cells with equimolar concentrations (5 μM) of 2-4 and cisplatin showed more efficient cellular uptake and DNA - fraction accumulation of complex 3 compared to complexes 2 and 4. Show less

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(ii) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy. Show less

An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane (pta) organoruthenium(II) complexes with methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level. Show less

In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-'ruthenium-cyclopentadienyl' conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7, MDA-MB-231) human cancer derived cell lines as well as in A2780cis, a cisplatin resistant cancer cell line. Our results show that all compounds have high activity towards cancer cells with low IC₅₀ values in the micromolar range. We observed that all Ru-PMC compounds are mainly found inside the cells, in contrast with the parental low molecular weight compound Ru1 that was mainly found at the membrane. All compounds induced mitochondrial alterations. PMC3 and Ru1 caused F-actin cytoskeleton morphology changes and reduced the clonogenic ability of the cells. The conjugate PMC3 induced apoptosis at low concentrations comparing to cisplatin and could overcame the platinum resistance of A2780cis cancer cells. A proteomic analysis showed that these compounds induce alterations in several cellular proteins which are related to the phenotypic disorders induced by them. Our results suggest that PMC3 is foreseen as a lead candidate to future studies and acting through a different mechanism of action than cisplatin. Here we established the potential of these Ru compounds as new metallodrugs for cancer chemotherapy. Show less

In this study, five ruthenium arene complexes with fluorene-bearing N,N-(1) and N,O-(2) donor Schiff base ligands were synthesized and fully characterized. Cationic ruthenium complexes 3[X], ([Ru(η⁶-C₆H₆)(Cl)(fluorene-N[double bond, length as m-dash]CH-pyridine)][X] (where X = BF₄, PF₆, BPh₄), were obtained by reacting ligand 1 with [Ru(η⁶-C₆H₆)Cl₂]₂ in the presence of NH₄X salts, whereas neutral complex 4, Ru(η⁶-C₆H₆)(Cl)(fluorene-N[double bond, length as m-dash]CH-naphtholate), was isolated by reacting ligand 2 with the same precursor. It was possible to obtain a cationic version of the latter, 5[BF₄], by reacting 4 with AgBF₄ in the presence of pyridine. All compounds were fully characterized by NMR and HR-ESI-MS whereas some of them were also analyzed by single crystal X-ray analysis. Their in vitro antiproliferative activity was also assessed in human breast cancer cell lines, notably MCF-7 and T47D. Complex 4 and its cationic counterpart 5[BF₄] were found to be the most cytotoxic compounds of the series (IC₅₀ = 6.2-16.2 μM) and displayed higher antiproliferative activities than cisplatin in both cell lines. It was found that 5[BF₄] undergoes a ligand exchange reaction and readily converts to 4 in the presence of 0.1 M NaCl, explaining the similarity in their observed cytotoxicities. Whereas 3[BF₄] and 3[PF₆] were found inactive at the tested concentrations, 3[BPh₄] displayed a considerable cytotoxicity (IC₅₀ = 16.7-27.8 μM). Notably, 3[BPh₄], 4 (and 5[BF₄]) were active against T47D, a cisplatin resistant cell line. Interestingly, 4 (16.4 μM) was found to be less cytotoxic than 3[BPh₄] and cisplatin (6.6 and 7.9 μM, respectively) in breast healthy cells (MCF-12A). However, in comparison to 4 and cisplatin (at 10 μM), a lower in vivo toxicity was observed for complex 3[BPh₄] on the development of zebrafish (Danio rerio) embryos. Show less

This paper describes the synthesis of new 6-aminoflavone (6AFl (3)) and 6-aminochromone (6AC (4)) complexes with Cu(ii) and Ru(ii) ions ([Cu(6AC)₂Cl₂] (3a), [Cu(6AFl)₂Cl₂] (4a), [Ru(p-cymene)(6AC)Cl₂] (4b)) and comparison of their properties with the previously described 7-aminoflavone (7AFl (1)) and 7-amino-2-methylchromone (7A2MC (2)) analogues. The cytotoxic effect of all these complexes against two human leukaemia cell lines (HL-60 and NALM-6), melanoma WM-115 cells and COLO205 cells, is determined. The cytotoxicity of copper(ii) complexes, especially [Cu(6AFl)₂Cl₂] (3a) was higher than ruthenium(ii) complexes with the same ligands. Their cytotoxic potency was also stronger in comparison to the referential agents like cisplatin. The pro-oxidative properties were determined for the most active complexes and their ability to generate ROS (reactive oxygen species)/RNS (reactive nitrogen species) in cancer cells was confirmed. The type of ligand and the chemical structure of the tested complexes had an influence on the level of ROS/RNS generated in cancer cells. The redox properties of the copper complex compounds were evaluated by cyclic voltammetry, and compared with the data for Ru(ii) complexes. The reduction and oxidation processes of Ru(iii)/Ru(ii) and Cu(ii)/Cu(i) were described as quasi-reversible. Show less