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Two copper(II) complexes (Cu-L1, Cu-L2) derived from 2,3-substituted quinazolinone Schiff base ligands (L1, L2) were prepared to examine their anticancer activity. Compounds were characterized using various spectroscopic methods (FTIR, NMR, UV-vis) and quantum-chemical calculations. The biological effects of Cu(II) complexes bearing quinazolinone scaffolds were evaluated on two cancers' cell lines (breast—MCF-7 and lung—A549), as well as on untransformed cells (keratinocytes—HaCaT). Copper complexes were highly cytotoxic, with IC50 in the low micromolar range, while the quinazoline ligands L1 and L2 remained inactive in inhibiting cell proliferation. Antioxidant activity was investigated in the model systems using DPPH and FRAP assays. The Cu-L1 and Cu-L2 complexes exhibited enhanced DPPH free radical scavenging efficiency compared to the L1 and L2 ligands, but their reducing ability was comparable to that of the free ligands. Evaluation of oxidative stress in vitro carried out by staining cells with various ROS-specific indicators showed reduced production of superoxide anion radical and hydrogen peroxide after treatment of cells with copper complexes. Such a negative impact on ROS formation in cells can lead to cellular redox imbalance and consequent cell death, among others, by inducing apoptosis and/or necrosis, depending on the copper complex used. We hypothesize that the high cytotoxic activity of the investigated copper complexes is apparently the result of multiple mechanisms of action, and the imbalance in the cellular antioxidant system partly contributes to the overall cytotoxic effect. [ABSTRACT FROM AUTHOR]

The use of polypyridyl Ru complexes to inhibit metastasis is a novel approach, and recent studies have shown promising results. We have reported recently that Ru (II) complexes gathering two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and the one being 2,2′-bipyridine (bpy) or its derivative with a 4-[3-(2-nitro-1H-imidazol-1-yl)propyl (bpy-NitroIm) or 5-(4-{4′-methyl-[2,2′-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moieties can alter the metastatic cascade, among others, by modulating cell adhesion properties. In this work, we show further studies of this group of complexes by evaluating their effect on HMEC-1 endothelial cells. While all the tested complexes significantly inhibited the endothelial cell migration, Ru-bpy additionally interrupted the pseudovessels formation. Functional changes in endothelial cells might arise from the impact of the studied compounds on cell elasticity and expression of proteins (vinculin and paxillin) involved in focal adhesions. Furthermore, molecular studies showed that complexes modulate the expression of cell adhesion molecules, which has been suggested to be one of the factors that mediate the activation of angiogenesis. Based on the performed studies, we can conclude that the investigated polypyridyl Ru (II) complexes can deregulate the functionality of endothelial cells which may lead to the inhibition of angiogenesis. [ABSTRACT FROM AUTHOR]

Primary tumor targeting is the dominant approach in drug development, while metastasis is the leading cause of cancer death. Therefore, in addition to the cytotoxic activity of a series of Ru(II) polypyridyl complexes of the type [Ru(dip)2L]2+ (dip: 4,7-diphenyl-1,10-phenanthroline while L = dip; bpy: 2,2′-bipyridine; bpy-SC: bipyridine derivative bearing a semicarbazone 2-formylopyridine moiety; dpq, dpq(CH3)2, dpb: quinoxaline derivatives) their ability to inhibit cell detachment was investigated. In vitro studies performed on lung cancer A549 cells showed that they accumulate in cells very well and exhibit moderate cytotoxicity with IC50 ranging from 4 to 13 µM. Three of the studied compounds that have dip, bpy-SC, or dpb ligands after treatment of the cells with a non-toxic dose (<1/2IC50) enhanced their adhesion properties demonstrated by lower detachment in the trypsin resistance assay. The same complexes inhibited both MMP-2 and MMP-9 enzyme activities with IC50 ranging from 2 to 12 µM; however, the MMP-9 inhibition was stronger. More detailed studies for [Ru(dip)2(bpy-SC)]2+, which induced the greatest increase in cell adhesion, revealed that it is predominately accumulated in the cytoskeletal fraction of A549 cells. Moreover, cells treated with this compound showed the localization of MMP-9 to a greater extent also in the cytoskeleton. Taken together, our results indicate the possibility of a reduction of metastatic cells escaping from the primary lesion to the surrounding tissue by prevention of their detachment and by influencing the activity of MMP-2 and MMP-9. [ABSTRACT FROM AUTHOR]

The mechanism of cell death induced by the ruthenium polypyridyl complexes comprising two 4,7-diphenyl-1,10-phenanthroline ligands as well as one unmodified 2,2′-bipyridyl or modified with 2-nitroimidazole moiety attached by shorter ( C 3 H 6 ) or longer ( C 6 H 12 ) linker was investigated. Cytotoxicity and proliferation assays revealed that the studied Ru polypyridyl complexes are more toxic against human pancreas carcinoma PANC-1 cell line than normal human keratinocytes HaCaT with IC 50 of 3–5 μM. The Ru complexes despite accumulation in mitochondria do not lead to mitochondrial disfunction, though decreasing of mitochondrial Ca 2 + causes mitochondria membrane hyperpolarization. The Ru polypyridyl conjugates induce some phenotypical characteristic of apoptosis, such as condensation of chromatin or phosphatidylserine translocation, however no caspase or calpain activation in the studied cell lines was observed, indicating that detected cell death does not occur via mitochondria- or ER-activated pathways. Caspase-independent cell death is caused by enormous ROS formation, mainly hydrogen peroxide and peroxyl radicals as well as by intracellular Ca 2 + homeostasis disruption. Accumulation of the Ru compounds inhibits the completion of DNA synthesis, arresting cells in S-phase of cell cycle. [ABSTRACT FROM AUTHOR]

A set of homoleptic ruthenium polypyridine (bipyridine and terpyridine) complexes flanked with several electron-donating pyrrolidine moieties has been characterized and the anticancer activity was evaluated toward human lung adenocarcinoma epithelial (A549) and murine colon carcinoma (CT26). Good antiproliferative effects were observed with an IC 50 ranging from ca. 4 to 21 μM against both cell lines. Dependence was found between the cytotoxicity, the lipophilicity and the Ru II /Ru III oxidation potential. All the studied compounds interacted quite well with albumin while the interaction with DNA was marginal. The biological studies revealed that the ruthenium complexes induced the ROS overproduction which might be one but not the only way of cell death induction. [ABSTRACT FROM AUTHOR]

We have developed a methodology for the microwave-assisted synthesis of tris-heteroleptic Ru(II) complexes. Three new Ru(II) complexes were synthesized with considerable cytotoxic and phototoxic activity. Their photoinduced toxicity is mainly based on the photogeneration of 1O 2 and H 2 O 2. The Ru complexes demonstrated high activity in inhibiting cancer cells, which was additionally enhanced by light activation of the compounds. [Display omitted] Ru(II) polypyridyl complexes are attracting particular attention as possible photodynamic therapy (PDT) agents due to their interesting photophysical properties, which can be easily tunable through the appropriate selection of attached ligands. However, blue-wavelength absorption of the complexes limited their potential application. In this study, three tris-heteroleptic Ru(II) polypyridyl complexes were synthesized to shift the absorption of the compounds toward longer wavelengths. Their photophysical, biological, and photodynamic properties were evaluated. The mechanism of the photoinduced toxicity was investigated by fluorescence and electron paramagnetic resonance (EPR) techniques in vitro and in aqueous solutions. The results revealed the photodynamic activity of the studied compounds is based mainly on the photogeneration of 1O 2 and H 2 O 2. Additionally, the synthesized Ru complexes demonstrated high activity in inhibiting the detachment of cancer cells. This effect was additionally enhanced by light activation of Ru compounds. The presented findings demonstrate a rational strategy for the efficient synthesis of tris-heteroleptic Ru(II) polypyridyl complexes to be used as promising photodynamic agents for cancer and antimetastatic treatments. [ABSTRACT FROM AUTHOR]

Abstract: A novel long-lifetime highly luminescent ruthenium polypyridyl complex containing 2-nitroimidazole moiety [Ru(dip)2(bpy-2-nitroIm)]Cl2 (dip=4,7-diphenyl-1,10-phenanthroline, bpy-2-nitroIm=4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-2,2′-bipyridine) has been designed cancer treatment and imaging. The luminescence properties of the synthesized compound strongly depend on the oxygen concentration. Under oxygen-free conditions quantum yield of luminescence and the average lifetime of emission were found to be 0.034 and 1.9μs, respectively, which is ca. three times higher in comparison to values obtained in air-equilibrated solution. The binding properties of the investigated ruthenium complex to human serum albumin have been studied and the apparent binding constant for the formation of the protein-ruthenium adduct was determined to be 1.1×105 M−1. The quantum yield and the average lifetime of emission are greatly enhanced upon binding of ruthenium compound to the protein. The DNA binding studies revealed two distinguished binding modes which lead to a decrease in luminescence intensity of ruthenium complex up to 60% for [DNA]/[Ru]<2, and enhancement of emission for [DNA]/[Ru]>80. Preliminary biological studies confirmed fast and efficient accumulation of the ruthenium complex inside cells. Furthermore, the ruthenium complex was found to be relatively cytotoxic with LD50 of 12 and 13μM for A549 and CT26 cell lines, respectively, under normoxic conditions. The retention and cellular uptake of ruthenium complex is enhanced under hypoxic conditions and its LD50 decreases to 8μM for A549 cell line. [Copyright &y& Elsevier]