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Three ruthenium complexes [RuCl(CTZ)(bipy)(P-P)]PF₆ [P-P=1,2-bis(diphenylphosphino)ethane (dppe-1), 1,4-bis(diphenylphosphino)butane (dppb-2) and 1,1'-bis(diphenylphosphino)ferrocene (dppf-3), bipy=2,2'-bipiridine and clotrimazole (CTZ) 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole] were synthesized. These complexes were characterized by a combination of elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, ¹H, ¹³C{¹H} and ³¹P{¹H} nuclear magnetic resonance techniques, cyclic voltammetry and mass spectroscopy. Bovine serum albumin binding constants, which were in the range of 1.30-36.00×10⁴M^-1, and thermodynamic parameters suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. DNA interactions studied by spectroscopic titration, viscosity measurements, gel electrophoresis, circular dichroism, ethidium bromide displacement and reactions with guanosine and guanosine monophosphate indicated the DNA binding affinity primarily through non-covalent interactions. All complexes 1-3 were tested against the human carcinoma cell lines MCF-7 (breast), A549 (lung) and DU-145 (prostate) presenting promising IC₅₀ values, between 0.50 and 14.00μM, in some cases lower than the IC₅₀ for the reference drug (cisplatin). The antimicrobial activity assays of the complexes provided evidence that they are potential agents against mycobacterial infections, specifically against Mycobacterium tuberculosis H37Rv. Show less

As one of the major cell regulated center, mitochondria are closely associated with cell proliferation, apoptosis of tumor cell. In this work, four new ruthenium (II) polypyridyl complexes [Ru(bpy)₂(FTTP)](ClO₄)₂ (1) (FTTP=11-(3-fluoro-naphthalen-2-yloxy)-4,5,9,14-tetraaza-benzo[b]triphenylene, bpy=2,2'-bipyridine), [Ru(phen)₂(FTTP)](ClO₄)₂ (2) (phen=1,10-phenanthroline), [Ru(bpy)₂(PTTP)](ClO₄)₂ (3) (PTTP=2-phenoxy-1,4,8,9-tetraazatriphenylene) and [Ru(phen)₂(PTTP)](ClO₄)₂ (4) were synthesized and characterized by elemental analysis, ESI-MS, ¹H NMR and ¹³C NMR. The cytotoxic activity, ability of inhibiting cell invasion, cell cycle arrest and apoptosis-inducing mechanism of these Ru(II) complexes have been investigated in detail by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method, invasion assay, comet assay as well as western blotting techniques. Notably, complexes 1-4 displayed high cytotoxic activity against liver carcinoma HepG2 cells and the IC₅₀ values of complexes 1-4 against HepG2 cells are 10.4±1.2, 9.3±0.6, 29.1±1.5 and 5.6±1.2μM, respectively. The comet assay showed that the complexes can induce DNA damage. The acridine orange (AO) and ethidium bromide (EB) staining method indicated that the complexes can cause apoptosis in HepG2 cells. Further studies showed that complexes 1-4 caused cell cycle arrest at G0/G1 phase and induced HepG2 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which involved an increase in the levels of reactive oxygen species (ROS), a decrease in the mitochondrial membrane potential, activation of caspases and Bcl-2 family proteins. Show less

Four new ruthenium(II) polypyridyl complexes [Ru(N-N)2(bddp)](ClO4)21-4 (N-N=dmb: 4,4'-dimethyl-2,2'-bipyridine 1, bpy: 2,2'-bipyridine 2, phen: 1,10-phenanthroline 3 and dmp: 2,9-dimethyl-1,10-phenanthroline 4, bddp=benzilo[2,3-b]-1,4-diazabenzo[i]dipyrido[3,2-a:2',3'-c]phenazine) were synthesized and characterized by elemental analysis, ESI-MS and (1)H NMR. The cytotoxicity in vitro of the complexes against BEL-7402, HeLa, MG-63 and A549 cell lines was investigated by MTT method. The complexes show high cytotoxic activity toward the selected cell lines with an IC50 value ranging from 5.3±0.6 to 15.7±3.6μM. The apoptosis was studied with acridine orange (AO)/ethdium bromide (EB) and Hoechst 33258 staining methods. The cellular uptake was investigated with DAPI staining method. The reactive oxygen species (ROS) and mitochondrial membrane potential were performed under fluorescent microscope and flow cytometry. The complexes can induce an increase in the ROS levels and a decrease in the mitochondrial membrane potential. The comet assay was studied with fluorescent microscope. The percentage in apoptotic and necrotic cells and cell cycle arrest were assayed by flow cytometry. The effects of the complexes on the expression of caspases and Bcl-2 family proteins were studied by western blot analysis. The results show that the complexes induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of Bcl-2 family proteins. Show less

The new carbazole N,N' ligand containing [(η(5)-C5Me5)MCl(L)]PF6, (M=Ir (1) and Rh (2)) and [(η(6)-C6H6)RuCl(L)]PF6 (3) (C5Me5=pentamethylcyclopentadienyl, L=9-ethyl-N-(pyridine-2-yl methylene)-9H-carbazole-3-amine) complexes has been synthesized and characterized by (1)H NMR, (13)C NMR, 2D NMR, melting point analysis, electronic absorption, infrared spectroscopy, HR-Mass spectroscopy and elemental analyses. The crystal structure of the [(η(5)-C5Me5)RhCl(L)]PF6 has been confirmed by single crystal XRD. The anticancer study of the synthesized complexes 1-3 clearly showed a potent inhibitor of human breast cancer cells (MCF-7) under in vitro conditions. The inhibitory concentrations (IC50) of the complexes 1-3 were determined at low (5, 6 and 8μM) concentration against the MCF-7 human breast cancer cell line. Further cytotoxic, cell cycle and nuclear studies confirmed that the novel half sandwich Ir(III), Rh(III) and Ru(II) complexes could be effective against MCF-7 human breast cancer cell proliferation. Moreover the results indicate that anticancer in vitro activity of complexes 1-3 falls in the order of 1>2>3. A molecular docking study of the complexes 1-3 showed the nature of binding energy, H-bond and hydrophobic interactions with the cyclooxygenase-2 (COX-2) receptor. Show less

A new pseudo-octahedral π-arene ruthenium(ii) piano-stool compound, containing an O,S-bidentate ligand (compound 1) and showing significant cytotoxic activity in vitro, was synthesized and characterized. In solution stability and interaction with the model protein bovine pancreatic ribonuclease (RNase A) were investigated by using UV-Vis absorption spectroscopy. Its crystal structure and that of the adduct formed upon reaction with RNase A were obtained by X-ray crystallography. The comparison between the structure of purified compound 1 and that of the fragment bound to RNase A reveals an unusual mode of protein binding that includes ligand exchange and alteration of coordination sphere geometry. Show less

Organelle-targeted photosensitizers have been reported to be effective photodynamic therapy (PDT) agents. In this work, we designed and synthesized two iridium(III) complexes that specifically stain the mitochondria and lysosomes of living cells, respectively. Both complexes exhibited long-lived phosphorescence, which is sensitive to oxygen quenching. The photocytotoxicity of the complexes was evaluated under normoxic and hypoxic conditions. The results showed that HeLa cells treated with the mitochondria-targeted complex maintained a slower respiration rate, leading to a higher intracellular oxygen level under hypoxia. As a result, this complex exhibited an improved PDT effect compared to the lysosome-targeted complex, especially under hypoxia conditions, suggestive of a higher practicable potential of mitochondria-targeted PDT agents in cancer therapy. Show less

Halogenido and carboxylato Ru(II) half-sandwich complexes of the general composition [Ru(η⁶-p-cym)(dpa)X]PF₆ (1-5) were prepared and thoroughly characterized with various techniques (e.g., mass spectrometry, NMR spectroscopy and X-ray analysis); dpa = 2,2'-dipyridylamine; p-cym = p-cymene; X = Cl^- (for 1), Br^- (for 2), I^- (for 3), valproate(1-) (for 4) or 4-phenylbutyrate(1-) (for 5). A single-crystal X-ray analysis showed a pseudo-octahedral piano-stool geometry of [Ru(η⁶-p-cym)(dpa)I]PF₆ (3), with a η⁶-coordinated p-cymene, bidentate N-donor dpa ligand and iodido ligand coordinated to the Ru(II) atom. The results of the ¹H-NMR solution behaviour studies proved that the complexes 1-5 hydrolyse were in the mixture of solvents used (10% MeOD-d₄/90% D₂O). Complexes 1-5 were in vitro inactive against the A2780 human ovarian carcinoma cell line, up to the highest tested concentration (IC₅₀ > 100 μM). Show less

Two new ruthenium (II) polypyridyl complexes [Ru(MeIm)₄(pip)]²⁺ (1) and [Ru(MeIm)₄(4-npip)]²⁺ (2) were synthesized under the guidance of computational studies (DFT). Their binding property to human telomeric G-quadruplex studied by UV-Vis absorption spectroscopy, the fluorescent resonance energy transfer (FRET) melting assay and circular dichroism (CD) spectroscopy for validating the theoretical prediction. Both of them were evaluated for their potential anti-proliferative activity against four human tumor cell lines. Complex 2 shows growth inhibition against all the cell lines tested, especially the human lung tumor cell (A549). The RTCA analysis not only validated the inhibition activity but also showed the ability of reducing A549 cells' migration. DNA-flow cytometric analysis, mitochondrial membrane potential (ΔΨm) and the scavenger measurements of reactive oxygen species (ROS) analysis carried out to investigate the mechanism of cell growth inhibition and apoptosis-inducing effect of complex 2. The results demonstrated that complex 2 induces tumor cells apoptosis by acting on both mitochondrial homeostasis destruction and death receptor signaling pathways. And those suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent against human tumor. Show less

A ruthenium(II) complex [Ru(p-cymene)(NHC)Cl2] (NHC=1,3-bis(4-(tert-butyl)benzylimidazol-2-ylidene), referred to as L-4, has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. The anticancer activity and mechanism of action of L-4 in human esophageal squamous carcinoma EC109 cells were systematically investigated. The results revealed that L-4 exerted strong inhibitory effect on the proliferation of EC109 cells, and it arrested EC109 cells at G2/M phase, accompanied with the up-regulation of p53 and p21 and the down-regulation of cyclin D1. The results also showed that the reactive oxygen species (ROS)-dependent apoptosis of EC109 can be induced by L-4 via inhibiting the activity of glutathione reductase (GR), decreasing the ratio of glutathione to oxidized glutathione (GSH/GSSG), and leading to the generation of reactive oxygen species. The mitochondria-mediated apoptosis of EC109 induced by L-4 was also observed from the increase of Bax/Bcl-2 ratio, overload of Ca(2+), disruption of mitochondrial membrane potential (MMP), redistribution of cytochrome c, and activation of caspase-3/-9. However, the effects of L-4 on the cell viability, GR activity, GSH/GSSG ratio, reactive oxygen species level, mitochondria dysfunction and apoptosis induction were remarkably attenuated by adding the reactive oxygen species scavenger, NAC. Therefore, it was concluded that L-4 can inhibit the proliferation of EC109 cells via blocking cell cycle progression and inducing reactive oxygen species-dependent and mitochondria-mediated apoptosis. These findings suggested that the ruthenium(II) complex might be a potential effective chemotherapeutic agent for human esophageal squamous carcinoma (ESCC) and worthy of further investigation. Show less

The four novel Ru(II) polypyridyl complexes of [Ru(Hdpa)2dmbip](2+) (1), [Ru(Hdpa)2NO2-dmbip](2+) (2), [Ru(Hdpa)2debip](2+) (3) and [Ru(Hdpa)2OH-debip](2+) (4) where Hdpa = 2,2'-bipyridylamine, dmbip = 2-(4-N,N-dimethylbenzenamine)1H-imidazo[4,5-f][1,10]phenanthroline, debip = 2-(4-N,N-diethylbenzenamine)1H-imidazo[4,5-f][1,10]phenanthroline, NO2-dmbip = NO2-2-(4-N,N-dimethylbenzenamine)1H-imidazo[4,5-f][1,10]phenanthroline, OH-debip = OH-2-(4-N,N-diethylbenzenamine)1H-imidazo[4,5-f][1,10]phenanthroline were synthesized and fully characterized using elemental analysis, Mass, NMR and FT-IR. The DNA binding behavior of all synthesized complexes were investigated by using electronic absorption spectra, emission spectra, cyclic light switch on and off, sensor studies, electrochemical method and viscosity titrations. Docking studies were performed with human DNA TOP1 by using LibDock. Furthermore explore antimicrobial activity, photocleavage and in vitro cytotoxicity assay of four Ru(II) complexes. Show less

A series of arene Ru(II) complexes coordinated with phenanthroimidazole derivatives, [(η⁶-C₆H₆)Ru(l)Cl]Cl(1b L = p-ClPIP = 2-(4-Chlorophenyl)imidazole[4,5f] 1,10-phenanthroline; 2b L = m-ClPIP = 2-(3-Chlorophenyl)imidazole[4,5f] 1,10-phenanthroline; 3b L = p-NPIP = 2-(4-Nitrophenyl)imidazole[4,5f] 1,10-phenanthroline; 4b L = m-NPIP = 2-(3-Nitrophenyl) imidazole [4,5f] 1,10-phenanthroline) were synthesized in yields of 89.9%-92.7% under conditions of microwave irradiation heating for 30 min to liberate four arene Ru(II) complexes (1b, 2b, 3b, 4b). The anti-tumor activity of 1b against various tumor cells was evaluated by MTT assay. The results indicated that this complex blocked the growth of human lung adenocarcinoma A549 cells with an IC₅₀ of 16.59 μM. Flow cytometric analysis showed that apoptosis of A549 cells was observed following treatment with 1b. Furthermore, the in vitro DNA-binding behaviors that were confirmed by spectroscopy indicated that 1b could selectively bind and stabilize bcl-2 G-quadruplex DNA to induce apoptosis of A549 cells. Therefore, the synthesized 1b has impressive bcl-2 G-quadruplex DNA-binding and stabilizing activities with potential applications in cancer chemotherapy. Show less

A series of Ru(ii)(η(6)-p-cymene) complexes (1-4) bearing the general formula [RuCl2(η(6)-p-cymene)L] (L = monodentate aroylthiourea ligand) has been synthesized and characterized by analytical and various spectroscopic techniques. The neutral monodentate coordination of aroylthiourea with Ru via an S atom was confirmed by single crystal X-ray diffraction study. The complexes were tested for their ability to interact with DNA and protein. The complexes bound with calf thymus DNA (CT DNA) with the intrinsic binding constant value in the order of 10(4) M(-1). The intercalative mode of binding was confirmed by the ethidium bromide (EB) displacement study. The interaction of the complexes with CT DNA was further supported by viscosity measurements and circular dichroic (CD) spectra. The Ru(ii) complexes cleaved the supercoiled DNA without the need of any external agent. The spectroscopic evidence showed good binding efficacy of the complexes with BSA (Bovine Serum Albumin). The alterations in the secondary structure of BSA by the Ru(ii) complexes were confirmed by synchronous fluorescence spectra. Cytotoxicity examination by MTT assay was carried out in two cancer cell lines (MCF7 and A549) and one non-cancerous cell line (L929). Complex 4 showed significant activity [IC50 = 52.3 (MCF7) and 54.6 (A549) μM] which was comparable with that of similar known complexes. The morphological changes assessed by Hoechst staining revealed that the cell death occurred by apoptosis. Show less

Lactate dehydrogenase (LDH) is a redox enzyme often overexpressed in cancer cells allowing their survival in stressful metabolic tumor environment. Ruthenium(II) complexes have been shown to impact on the activity of purified horseradish peroxidase and glucose oxidase but the physiological relevance remains unclear. In this study we investigated how ruthenium complexes impact on the activity of LDH in vitro and in cancer cells and performed a comparative study using polypyridine ruthenium(II) complex [Ru(bpy)₃]²⁺ (1) and its structurally related cyclometalated 2-phenylpyridinato counterpart [Ru(phpy)(bpy)₂]⁺ (2) (bpy=2,2'-bipyridine, phpyH=2-phenylpyridine). We show that the cytotoxicity in gastric and colon cancer cells induced by 2 is significantly higher compared to 1. The kinetic inhibition mechanisms on purified LDH and the corresponding inhibition constants K_i or i_0.5 values were calculated. Though complexes 1 and 2 are structurally very similar (one Ru-C bond in 2 replaces one Ru-N bond in 1), their inhibition modes are different. Cyclometalated complex 2 behaves exclusively as a non-competitive inhibitor of LDH from rabbit muscle (LDH_rm), strongly suggesting that 2 does not interact with LDH in the vicinities of either lactate/pyruvate or NAD⁺/NADH binding sites. Sites of interaction of 1 and 2 with LDH_rm were revealed theoretically through computational molecular docking. Inhibition of LDH activity by 2 was confirmed in cancer cells. Altogether, these results revealed an inhibition of LDH activity by ruthenium complex through a direct interaction structurally tuned by a Ru-C bond. Show less

Two Ru(II) complexes [Ru(phen)2bppp](ClO4)2 (1) and [Ru(phen)27-Br-dppz](ClO4)2 (2) [phen=1,10 phenanthroline, 7-Br-dppz=7-fluorodipyrido[3,2-a:2',3'-c]phenazine, bppp=11-bromo-pyrido[2',3':5,6]pyrazino[2,3-f] [1,10]phenanthroline] have been synthesized and characterized by elemental analysis, ES-MS, (1)H-NMR, (13)C-NMR and IR. The in vitro cytotoxicity of the complexes examined against a panel of cancer cell lines (HeLa, Du145 and A549) by MTT method, both complexes show prominent anticancer activity against various cancer cells. Live cell imaging study and flow cytometric analysis demonstrate that both the complexes 1 and 2 could cross the cell membrane accumulating in the nucleus. Further, flow cytometry experiments showed that the cytotoxic Ru(II) complexes 1 and 2 induced apoptosis of HeLa tumor cell lines. Photo induced DNA cleavage studies have been performed and results indicate that both the complexes efficiently photo cleave pBR322 DNA. The binding properties of two complexes toward CT-DNA were investigated by various optical methods and viscosity measurements. The experimental results suggested that both Ru(II) complexes can intercalate into DNA base pairs. The complexes were docked into DNA-base pairs using the GOLD docking program. Show less

Anticancer active metal complexes with biologically active ligands have the potential to interact with more than one biological target, which could help to overcome acquired and/or intrinsic resistance of tumors to small molecule drugs. In this paper we present the preparation of 2-hydroxy-[1,4]-naphthoquinone-derived ligands and their coordination to a Ru(II)(η(6)-p-cymene)Cl moiety. The synthesis of oxime derivatives resulted in the surprising formation of nitroso-naphthalene complexes, as confirmed by X-ray diffraction analysis. The compounds were shown to be stable in aqueous solution but reacted with glutathione and ascorbic acid rather than undergoing reduction. One-electron reduction with pulse radiolysis revealed different behavior for the naphthoquinone and nitroso-naphthalene complexes, which was also observed in in vitro anticancer assays. Show less

Two ruthenium(II) complexes containing guanidinium ligands have been synthesized and characterized for the first time. It was found that the two complexes exhibit moderate antitumor activity in Hela, A549, CNE-2, MCF-7, and HepG2 human tumor cells. Flow cytometric analysis showed that both complexes arrested the cell cycle in the G2/M phase and induced apoptosis in Hela cells. Mechanism studies indicate that both complexes induced apoptosis through caspase- and reactive oxygen species (ROS)-dependent pathways. Additionally, the two complexes displayed higher phototoxicity to tumor cells and almost no influence on normal liver LO2 cells upon irradiation at 450nm. Show less

A Ru(ii) arene complex with a NO-releasing 4-nitrooxymethyl-pyridine ligand shows increased cytotoxicity against the non-small cell lung cancer cell line A549 as compared to either the free ligand or the unfunctionalized complex. EPR spin-trapping studies show that NO release is selective, being limited in phosphate buffered saline or human serum, but promoted by glutathione. Show less

Three new ruthenium(II)-arene complexes, namely [(η(6)-p-cymene)Ru(Me2dppz)Cl]PF6 (1), [(η(6)-benzene)Ru(Me2dppz)Cl]PF6 (2) and [(η(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me2dppz=11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip=2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin. Show less