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Compounds capable of light-triggered cytotoxicity are appealing potential therapeutics, because they can provide spatial and temporal control over cell killing to reduce side effects in cancer therapy. Two simple homoleptic Ru(II) polypyridyl complexes with almost-identical photophysical properties but radically different physiochemical properties were investigated as agents for photodynamic therapy (PDT). The two complexes were identical, except for the incorporation of six sulfonic acids into the ligands of one complex, resulting in a compound carrying an overall -4 charge. The negatively charged compound exhibited significant light-mediated cytotoxicity, and, importantly, the negative charges resulted in radical alterations of the biological activity, compared to the positively charged analogue, including complete abrogation of toxicity in the dark. The charges also altered the subcellular localization properties, mechanism of action, and even the mechanism of cell death. The incorporation of negative charged ligands provides a simple chemical approach to modify the biological properties of light-activated Ru(II) cytotoxic agents. Show less

A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed. Show less

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells. Show less

Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. Show less

Here, we examine the photophysical properties of five ruthenium(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and functionalized bipyridine (R₁bpy-R₂, where R₁= H or CH3, R₂= H, CH₃, COO⁻,4-[3-(2-nitro-1H-imidazol-1-yl)propyl] or 1,3-dicyclohexyl-1-carbonyl-urea) towards development of luminescence probes for cellular imaging. These complexes have been shown to interact with albumin and the formed adducts exhibited up to eightfold increase in the luminescence quantum yield as well as the average lifetime of emission. It was demonstrated that they cannot bind to DNA through the intercalation mode and its luminescence in the presence of DNA is quenching. Cell viability experiments indicated that all complexes possess significant dose-dependent cytotoxicity (with IC₅₀ 5-19 μM) on 4T1 breast cancer cell line and their anti-proliferative activity correlates very well with their lipophilicity. Cellular uptake was studied by measuring the ruthenium content in cells using ICP-MS technique. As expected, the better uptake is directly related to higher lipophilicity of doubly charged ruthenium complexes while uptake of monocationic one is much lower in spite of the highest lipophilicity. Additionally staining properties were assessed using flow cytometry and fluorescence microscopy. These experiments showed that complex with 1,3-dicyclohexyl-1-carbonyl-urea substituent exhibits the best staining properties in spite of the lowest luminescence quantum yield in buffered solution (pH 7.4). Our results point out that both the imaging and cytotoxic properties of the studied ruthenium complexes are strongly influence by the level of internalization and protein interaction. Show less

KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models. Show less

Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) 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 cross-resistant 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. Show less

Organometallic Ru(II), Os(II) and Rh(III) complexes of lapachol induce apoptosis in human tumour cell lines in the low μM range by a mode of action involving oxidative stress, especially in the case of the ruthenium compound. Show less

Two functional Ru(II) mixed-ligand complexes, [Ru(phen)(2)(ttbd)](2+) (1) (ttbd = 4-(6-propenyl-pyrido[3,2-a]phenzain-10-yl-benzene-1,2-diamine, phen = 1,10-phenanthroline) and [Ru(bpy)(2)(ttbd)](2+) (2) (bpy = 2,2'-bipyridine), have been synthesized and characterized. The spectral characteristics of complexes 1 and 2 were investigated using fluorescence spectroscopy and revealed that both complexes were very sensitive to solvent polarity and oxygen molecules in nonaqueous solvents. The binding properties of the two complexes towards calf thymus DNA (CT-DNA) were investigated with different spectrophotometric methods, viscosity measurements and quantum chemistry calculations, indicating that both complexes could enantioselectively bind to CT-DNA by means of intercalation, but with different binding strengths and discrimination. On the other hand, the cytotoxicity of both complexes have been evaluated by MTT assays and Giemsa staining experiments. The main results reveal that the hydrophobicity and surface area of the ancillary ligands have a significant effect on their DNA binding behavior and both complexes are likely to be useful for optically probing nonaqueous and oxygen-free environments. Show less

Organometallic compounds which contain metals, such as ruthenium or gold, have been investigated as a replacement for platinum-derived anticancer drugs. They often show good antitumor effects, but the identification of their precise mode of action or their pharmacological optimization is still challenging. We have previously described a class of ruthenium(II) compounds with interesting anticancer properties. In comparison to cisplatin, these molecules have lower side effects, a reduced ability to interact with DNA, and they induce cell death in absence of p53 through CHOP/DDIT3. We have now optimized these molecules by improving their cytotoxicity and their water solubility. In this article, we demonstrate that by changing the ligands around the ruthenium we modify the ability of the compounds to interact with DNA. We show that these optimized molecules reduce tumor growth in different mouse models and retain their ability to induce CHOP/DDIT3. However, they are more potent inducers of cancer cell death and trigger the production of reactive oxygen species and the activation of caspase 8. More importantly, we show that blocking reactive oxygen species production or caspase 8 activity reduces significantly the activity of the compounds. Altogether our data suggest that water-soluble ruthenium(II)-derived compounds represent an interesting class of molecules that, depending on their structures, can target several pro-apoptotic signaling pathways leading to reactive oxygen species production and caspase 8 activation. Show less

A series of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), HOC(6)H(4)CHN-NHCONR(2), and their rhenium(I) tricarbonyl complexes, [ReBr(CO)(3)(SSC)], have been synthesised and characterised by IR and (1)H NMR spectroscopy. Crystallographic analysis of the complex [ReBr(CO)(3)(H(2)Bu(2))] (H(2)Bu(2)=SSC where R=Bu(n)) showed that the SSC acts as a bidentate ligand via its imino nitrogen and carbonyl oxygen atoms. The [ReBr(CO)(3)(SSC)] complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells (IC(50)=1-24μM, cf. 18μM for cisplatin), and the majority of them are virtually non-toxic against non-cancerous human fibroblasts. Apoptotic assays of [ReBr(CO)(3)(H(2)Bnz(2))] (Bnz=benzyl) revealed that it mediates cytotoxicity in MOLT-4 cells via apoptosis. The complex [ReBr(CO)(3)(H(2)Bnz(2))] reacts with guanosine by proton transfer from the phenolic OH group to N(7) of guanosine. In (CD(3))(2)SO, [ReBr(CO)(3)(H(2)Bnz(2))] undergoes facile conversion to the dimeric complex, [Re(CO)(3)(HBnz(2))](2), via bromide dissociation. Show less

In an attempt to combine the ability of indolobenzazepines (paullones) to inhibit cyclin-dependent kinases (Cdks) and that of platinum-group metal ions to interact with proteins and DNA, ruthenium(II) and osmium(II) arene complexes with paullones were prepared, expecting synergies and an increase of solubility of paullones. Complexes with the general formula [M(II)Cl(η(6)-p-cymene)L]Cl, where M=Ru (1, 3) or Os (2, 4), and L=L(1) (1, 2) or L(2) (3, 4), L(1)=N-(9-bromo-7,12-dihydroindolo[3,2-d][1]-benzazepin-6(5H)-yliden-N'-(2-hydroxybenzylidene)azine and L(2)=N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6-yl)-N'-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl-methylene]azinium chloride (L(2)(*)HCl), were now investigated regarding cytotoxicity and accumulation in cancer cells, impact on the cell cycle, capacity of inhibiting DNA synthesis and inducing apoptosis as well as their ability to inhibit Cdk activity. The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay yielded IC(50) values in the nanomolar to low micromolar range. In accordance with cytotoxicity data, the BrdU assay showed that 1 is the most and 4 the least effective of these compounds regarding inhibition of DNA synthesis. Effects on the cell cycle are minor, although concentration-dependent inhibition of Cdk2/cyclin E activity was observed in cell-free experiments. Induction of apoptosis is most pronounced for complex 1, accompanied by a low fraction of necrotic cells, as observed by annexin V-fluorescein isothiocyanate/propidium iodide staining and flow cytometric analysis. Show less

Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (1c-5c) of the general formula [RuCl(η(6)-arene)(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η(6)-benzylamide and L is a Cdk inhibitor [3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) and indolo[3,2-d]benzazepines (L4 and L5)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2-3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of 1c and 2c(-HCl) afforded residues, which after recrystallization from EtOH and EtOH/H(2)O, respectively, were shown by X-ray diffraction to be cis,cis-[Ru(II)Cl(2)(DMSO)(2)(L1)]·H(2)O and mer-[Ru(II)Cl(DMSO)(3)(L2-H)]·H(2)O. Compound 5c, with a coordinated amidine unit, undergoes E/Z isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes 1c-5c are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, 1c-5c were conjugated to recombinant human serum albumin, potentially exploiting the so-called "enhanced permeability and retention" effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases. Show less

A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)(2)H][trans-RuCl(4)(DMSO)(2)] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl(4)(DMSO)(n-Cl-LH)]⋅xSol (1-3), trans-[RuCl(4)(DMSO)(n-Br-LH)]·xSol (4-6), trans-[RuCl(4)(DMSO)(n-OMe-LH)]·xSol (7-9) and trans-[RuCl(4)(DMSO)(n-OH-LH)]·xSol (10-12); n=2, 3, and 4, x=0-1.5; and Sol = H(2)O, DMSO, EtOH and/or (Me)(2)CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES+(positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl(4)(DMSO)(3-Br-LH)]⋅(Me)(2)CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC(50)>100μM in contrast to the moderate results regarding the antiradical activity with IC(50)≈10(-3)M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ. Show less

The cytotoxicity, hydrophobicity (log P), cellular uptake, aqueous reactivity, and extent of DNA adduct formation in the A2780 ovarian carcinoma cells for four osmium(II) arene complexes [(eta(6)-arene)Os(4-methyl-picolinate)Cl] that differ only in their arene ligands as benzene (1), p-cymene (2), biphenyl (3), or tetrahydroanthracene (4) are reported. There is a correlation between hydrophobicity (log P), cellular uptake, nucleus uptake, and cytotoxicity of the complexes, following the order 3 approximately 4 > 2 > 1, suggesting that the arene plays an important role in the biological activity of these types of compounds. Cell distribution studies using fractionation showed that all four compounds distribute similarly within cells. DNA binding of osmium did not correlate with cytotoxicity, indicating that the nature of the DNA lesion may also be crucial to activity. TEM images of ovarian cells treated with 3 revealed morphological changes associated with apoptosis with possible involvement of mitochondria. Show less

The ruthenium compound KP1019 has demonstrated promising anticancer activity in a pilot clinical trial. This study aims to evaluate the intracellular uptake/binding patterns of KP1019 and its sodium salt KP1339, which is currently in a phase I-IIa study. Although KP1339 tended to be moderately less cytotoxic than KP1019, IC(50) values in several cancer cell models revealed significant correlation of the cytotoxicity profiles, suggesting similar targets for the two drugs. Accordingly, both drugs activated apoptosis, indicated by caspase activation via comparable pathways. Drug uptake determined by inductively coupled plasma mass spectrometry (ICP-MS) was completed after 1 h, corresponding to full cytotoxicity as early as after 3 h of drug exposure. Surprisingly, the total cellular drug uptake did not correlate with cytotoxicity. However, distinct differences in intracellular distribution patterns suggested that the major targets for the two ruthenium drugs are cytosolic rather than nuclear. Consequently, drug-protein binding in cytosolic fractions of drug-treated cells was analyzed by native size-exclusion chromatography (SEC) coupled online with ICP-MS. Ruthenium-protein binding of KP1019- and KP1339-treated cells distinctly differed from the platinum binding pattern observed after cisplatin treatment. An adapted SEC-SEC-ICP-MS system identified large protein complexes/aggregates above 700 kDa as initial major binding partners in the cytosol, followed by ruthenium redistribution to the soluble protein weight fraction below 40 kDa. Taken together, our data indicate that KP1019 and KP1339 rapidly enter tumor cells, followed by binding to larger protein complexes/organelles. The different protein binding patterns as compared with those for cisplatin suggest specific protein targets and consequently a unique mode of action for the ruthenium drugs investigated. Show less

Four ruthenium(II) complexes with the formula [Ru(η(5)-C(5)H(5))(PP)L][CF(3)SO(3)], being (PP = two triphenylphosphine molecules), L = 1-benzylimidazole, ; (PP = two triphenylphosphine molecules), L = 2,2'bipyridine, ; (PP = two triphenylphosphine molecules), L = 4-Methylpyridine, ; (PP = 1,2-bis(diphenylphosphine)ethane), L = 4-Methylpyridine, , were prepared, in view to evaluate their potentialities as antitumor agents. The compounds were completely characterized by NMR spectroscopy and their crystal and molecular structures were determined by X-ray diffraction. Electrochemical studies were carried out giving for all the compounds quasi-reversible processes. The images obtained by atomic force microscopy (AFM) suggest interaction with pBR322 plasmid DNA. Measurements of the viscosity of solutions of free DNA and DNA incubated with different concentrations of the compounds confirmed this interaction. The cytotoxicity of compounds 1234 was much higher than that of cisplatin against human leukemia cancer cells (HL-60 cells). IC(50) values for all the compounds are in the range of submicromolar amounts. Apoptotic death percentage was also studied resulting similar than that of cisplatin. Show less

A new ligand DBHIP and its two ruthenium (II) complexes [Ru(bpy)(2)(DBHIP)](ClO(4))(2) (1) and [Ru(phen)(2)(DBHIP)](ClO(4))(2) (2) have been synthesized and characterized. The binding behaviors of the two complexes to calf thymus DNA were investigated by absorption spectra, viscosity measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants for complexes 1 and 2 have been determined to be 8.87+/-0.27 x 10(4)M(-1) (s=1.83) and 1.32+/-0.31 x 10(5)M(-1) (s=1.84). The results suggest that these complexes interact with DNA through intercalative mode. The cytotoxicity of DBHIP, complexes 1 and 2 has been evaluated by MTT assay. The apoptosis assay was carried out with acridine orange/ethidium bromide (AO/EB) staining methods. The studies on the mechanism of photocleavage demonstrate that superoxide anion radical (O(2)(-)) and singlet oxygen ((1)O(2)) may play an important role. Show less

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(I) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X = Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R = p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N'-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N'-chelating ligands for all Re(I) complexes. Biological activity of four oximine rhenium(I) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(I) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity. Show less

Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC(50) values of 1 and 2 toward HT-29 cells increase from 0.19 and 0.069 microM on immediate use in the dark to 0.66 and 0.312 microM, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer-[IrX(3)(DMSO)(phen)] (X=Cl 7, Br 8) are significantly less cytotoxic than their facial Ir(III) polypyridyl counterparts: IC(50)=20.3 microM for 7 and 4.6 microM for fac-[IrCl(3)(DMSO)(phen)] 5 toward MCF-7 cells. The IC(50) values for the complexes fac-[IrX(3)(L)(pp)] 9-13 decrease in the orders: a) Cl>Br for X and b) H(2)O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM-6) and lymphoma (BJAB) cells after incubation with 2, 3, and 11 (X=Br, L=H(2)O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible. Show less

A novel series of ionic Ru(II) arene Cp* sandwich complexes has been synthesized and characterized. Screening results for cytotoxicity against a range of human tumor cell lines and normal human cells indicate that the complexes show promising anticancer activity, which varies with changes in the arene ligand and the anionic counterion. Show less

[Ru(tBu2bpy)2(2-appt)](PF6)2 [1.(PF6)2, tBu2bpy = 4,4'-di-tert-butyl-2,2'-bipyridine, 2-appt = 2-amino-4-phenylamino-6-(2-pyridyl)-1,3,5-triazine] and [Re(CO)3(2-appt)Cl] (2) were prepared and characterized by X-ray crystal analysis. The binding of 1.(PF6)2 and 2 to calf thymus DNA (ct DNA) led to increases in the DNA melting temperature (Delta Tm = +12 degrees C), modest hypochromism (29% and 5% of the absorption bands at lambda max = 450 and 376 nm, respectively), and insignificant shifts in the absorption maxima. The binding constants of 1.(PF6)2 and 2 with ct DNA, as determined by absorption titration, are (8.9 +/- 0.5) x 104 and (3.6 +/- 0.1) x 104 dm3 mol-1, respectively. UV-vis absorption titration, DNA melting studies, and competition dialysis using synthetic oligonucleotides [poly(dA-dT)2 and poly(dG-dC)2] revealed that 1.(PF6)2 and 2 exhibit a binding preference for AT sequences. A modeling study on the interaction between 1 or 2 and B-DNA revealed that the minor groove is the most favored binding site and an extensive hydrogen-bonding network is formed. As determined by MTT assays, 1.(PF6)2 and 2 exhibited moderate cytotoxicities toward several human cancer cell lines (KB-3-1, HepG2, and HeLa), as well as a multi-drug-resistant cancer cell line (KB-V-1). According to confocal microscopic and flow cytometric studies, 1.(PF6)2 and 2 induced apoptosis (50-60%) in cancer cells with <5% necrosis detected. Show less