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A series of ferrocene and (arene)ruthenium(II) complexes attached to the naturally occurring anticancer naphthoquinones plumbagin and juglone was tested for efficacy against various cancer cell lines and for alterations in the mode of action. The plumbagin ferrocene and (p-cymene)Ru(II) conjugates 1c and 2a overcame the multi-drug drug resistance of KB-V1/Vbl cervix carcinoma cells and showed IC50 (72 h) values around 1 μM in growth inhibition assays using 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT). They were further investigated for their influence on the cell cycle of KB-V1/Vbl and HCT-116 colon carcinoma cells, on the generation of reactive oxygen species (ROS) by the latter cell line, for their substrate character for the P-glycoprotein drug eflux pump via the calcein-AM efflux assays, and for DNA affinity by the electrophoretic mobility shift assay (EMSA). The derivatives 1c and 2a increased the number of dead cancer cells (sub-G0/G1 fraction) in a dose- and time-dependent manner. ROS levels were significantly increased upon treatment with 1c and 2a. These compounds also showed a greater affinity to linear DNA than plumbagin. While plumbagin did not affect calcein-AM transport by P-glycoprotein the derivatives 1c and 2a exhibited a 50% or 80% inhibition of the P-glycoprotein-mediated calcein-AM efflux relative to the clinically established sensitizer verapamil. Show less

A new series of monoselenoquinone and diselenoquinone π complexes, [(η(6) -p-cymene)Ru(η(4) -C6 R4 SeE)] (R=H, E=Se (6); R=CH3 , E=Se (7); R=H, E=O (8)), as well as selenolate π complexes [(η(6) -p-cymene)Ru(η(5) -C6 H3 R2 Se)][SbF6 ] (R=H (9); R=CH3 (10)), stabilized by arene ruthenium moieties were prepared in good yields through nucleophilic substitution reactions from dichlorinated-arene and hydroxymonochlorinated-arene ruthenium complexes [(η(6) -p-cymene)Ru(C6 R4 XCl)][SbF6 ]2 (R=H, X=Cl (1); R=CH3 , X=Cl (2); R=H, X=OH (3)) as well as the monochlorinated π complexes [(η(6) -p-cymene)Ru(η(5) -C6 H3 R2 Cl)][SbF6 ]2 (R=H (4); R=CH3 (5)). The X-ray crystallographic structures of two of the compounds, [(η(6) -p-cymene)Ru(η(4) -C6 Me4 Se2 )] (7) and [(η(6) -p-cymene)Ru(η(4) -C6 H4 SeO)] (8), were determined. The structures confirm the identity of the target compounds and ascertain the coordination mode of these unprecedented ruthenium π complexes of selenoquinones. Furthermore, these new compounds display relevant cytotoxic properties towards human ovarian cancer cells. Show less

Mitochondria-targeted compounds represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three cyclometalated iridium(III) complexes (1-3) containing bis-N-heterocyclic carbene (NHC) ligands have been explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophysical properties, which greatly facilitates the study of their intracellular fate. All three complexes are more cytotoxic than cisplatin against the cancer cells screened. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Additionally, they display up to 3 orders of magnitude higher cytotoxicity upon irradiation at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes. Show less

Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds. Show less

The ruthenium DMSO complexes cis-Ru(II)C12(DMSO)4 and [(DMSO)2H][trans-Ru(III)Cl4(DMSO)2] reacted with 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline (L1), 4-(3'-chloro-4'-fluoroanilino)-6-(2-(1H-imidazol-1-yl)ethoxy)-7-methoxy quinazoline (L2), N-(benzo[d]imidazol-4-yl)-6,7-dimethoxyquinazolin-4-amine hydrochloride (L3), 5-(6,7-dimethoxyquinazolin-4-ylamino)quinolin-8-ol hydrochloride (L4), respectively, to afford [Ru(II)Cl2(DMSO)2(L1)] (1), [Ru(III)Cl3(DMSO)(L1)] (2), [Ru(III)Cl4(DMSO)(H-L2)] (3), [Ru(III)Cl4(DMSO)(H-L3)] (4), and [Ru(III)Cl3(DMSO)(H-L4)] (5), which were characterised by mass spectrometry, NMR, elementary analysis and single crystal X-ray diffraction (complex 1). Experimental screening (ELISA) showed that complexes 1, 2 and 3 are remarkably inhibitory towards epidermal growth factor receptor (EGFR) with IC50 values at submicromolar or nanomolar level. Docking studies indicated that complexation with ruthenium has little interference with the formation of the two essential H-bonds between the N3 of the quinazoline ring in L1 and L2 and O-H of Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769 in EGFR. Moreover, complex 2 was shown to be more active against the EGF-stimulated proliferation of human breast cancer cell line MCF-7 than the better EGFR inhibitor 4-(3'-chloro-4'-fluoroanilino)-6,7-dimethoxyquinazoline, being more potential to induce early-stage apoptosis than gefitinib. These imply that apart from inhibiting EGFR, complex 2 may involve in regulating other biological events related to the proliferation of MCF-7, implicating a novel type of multi-targeting metal-based anticancer 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

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

The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal-based, three-component assembly reaction for the synthesis of a library of 442 Ru-arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one-pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(η6-1,3,5-triisopropylbenzene)RuCl(4-methoxy-N-(2-quinolinylmethylene)aniline)]Cl (4) displayed low micromolar IC50 values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC50 value between p53+/+ and p53-/- cells suggests that 4 and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer. 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

Transition metal complexes with dual functions of DNA photobinding via coordination and DNA photocleavage via(1)O2 may present potent antitumor activities with high selectivity and a wide anticancer spectrum. We herein report such a complex, [(η(6)-p-cymene)Ru(dpb)(py)](2+) (dpb = 2,3-bis(2-pyridyl)benzoquinoxaline, py = pyridine, 1). The highly delocalized nature of dpb provides 1 with long wavelength-absorbing properties and a long-lived excited state, facilitating (1)O2 generation. Additionally, the bulky nature of dpb leads to a distorted coordination geometry, and allow the (3)MC (metal-centered) state to be more accessible. From this, dissociation of py and dpb may occur, followed by the coordination of the resultant Ru fragment to nucleic bases if DNA is present. The dissociation of dpb can turn on fluorescence of its own, enabling real-time imaging of the photoactivation process. The fascinating properties of 1 and the underlying mechanisms that occur may provide guidelines for developing more efficient metallodrugs with dual potential for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Show less

Studies have shown that ruthenium complexes have relatively strong anticancer activity, cell uptake of drugs have a crucial impact on the pharmacological activity, using autofluorescence of ruthenium complexes could effectively track cancer cells and drug distribution, transport accurately in real time. In this work, we present the synthesis and detailed characterization of two novel Ru(II) complexes with hydrophobic ancillary ligands, namely [Ru(bpy)2(5-idip)](2+) (RBD) and [Ru(phen)2(5-idip)](2+) (RPD) (5-idip = 2-indole-[4,5-f][1,10]phenanthroline). We have shown that RPD can enter the HeLa cells efficiently through non-endocytotic, but energy-dependent mechanism and first accumulated in lysosomes, and then escape from the lysosomes and localize within the nuclei, efficiently lead to the inhibition of DNA transcription and translation and induced cell apoptosis. Further studies on the mechanism of apoptosis in HeLa cells demonstrate that RPD is able to induce mitochondria-mediated apoptosis in HeLa cells through activation of initiator caspase-9 and down-stream effector caspase-3 and -7 and cleavage of PARP. We have also demonstrated that RPD bind to telomeric G-quadruplex DNA effectively and selectively, together with increased p21 and p16 expression. Our findings suggest that RPD induces HeLa cell apoptosis through mitochondria-mediated pathway and inhibition of telomerase activity. RPD may be a candidate for further evaluation as a chemotherapeutic agent for human cancers. Show less

Heteroleptic C^N cyclometalated iridium(iii) complexes incorporating a monostyryl/distyryl BODIPY ligand via acetylide bonds of 2,2'-bipyridine (bpy) with both absorption (ca. ε = 8.96 × 10⁴ M^-1 cm^-1, 9.89 × 10⁴ M^-1 cm^-1, and 7.89 × 10⁴ M^-1 cm^-1 at 664 nm, 644 nm, and 729 nm for Ir-2, Ir-3 and Ir-4, respectively) and fluorescence emission bands (ca. 624-794 nm for Ir-1, Ir-2, Ir-3 and Ir-4) in the near infra-red region (NIR) and exceptionally long-lived triplet excited states (τ = 156.5 μs for Ir-2) have been reported. Ir(ppy)₃ (Ir-0; ppy = 2-phenylpyridine) was used as reference, which gives the typical weak absorption in visible range (ε = 1.51 × 10⁴ M^-1 cm^-1 M^-1 cm^-1 at 385 nm). The nanosecond time-resolved transient absorption and DFT calculations proposed that styryl BODIPY-localized long lived ³IL states were populated for Ir-1, Ir-2, Ir-3 and Ir-4 (τ_T = 106.6 μs, 156.5 μs, 92.5 μs and 31.4 μs, respectively) upon photoexcitation. The complexes were used as triplet photosensitizers for singlet oxygen (¹O₂) mediated photooxidation of 1,5-dihydronaphthalene to produce juglone. The ¹O₂ quantum yields (Φ_Δ) of Ir-1 (0.53) and Ir-2 (0.81) are ca. 9-fold of Ir-3 (0.06) and 40-fold of Ir-4 (0.02), respectively. Ir-2 has high molar absorption coefficient at 664 nm, moderate fluorescence in the NIR region, and high singlet oxygen quantum yield (Φ_Δ = 0.81), exhibits predominate photocytotoxicity over dark cytotoxicity in LLC cells (lung cancer cells) upon irradiation, making it potentially suitable for use in in vivo photodynamic therapy (PDT). Our results are useful for preparation of transition metal complexes that show strong absorption of visible light in the NIR region with long-lived triplet excited states and for the application of these complexes in photocatalysis and theranostics such as simultaneous photodynamic therapy (PDT) and luminescent bioimaging. Show less

Two ruthenium(II) polypyridyl complexes, [Ru(dppz)2dppz-11-CO2Me](ClO4)2 (Ru1) and [Ru(dppz)3](ClO4)2 (Ru2), have been synthesized and characterized. The spectral characteristics of Ru1 and Ru2 were investigated by fluorescence spectroscopy and revealed that both complexes were sensitive to solvent polarity. The binding properties of the two complexes towards calf-thymus DNA (CT-DNA) have been investigated by different spectrophotometric methods and viscosity measurements, indicating that both complexes bind to CT-DNA by means of intercalation, but with different binding affinities. Topoisomerase inhibition and DNA strand passage assay demonstrates that the two complexes are dual inhibitors of topoisomerases I and IIa. On the other hand, the cytotoxicity of both complexes has been evaluated by MTT assays and Giemsa staining experiments. The main results reveal that the ester functional group has a significant effect on the DNA-binding affinities and topoisomerases inhibition effects of Ru1 and Ru2, and further advance our knowledge on the DNA-binding and topoisomerase inhibition by Ru(II) complexes. Show less

A new Ru(II)-Se complex, Ru(bpy)2L2Cl2 (bpy = 2,2'-bipyridine, L = 1,10-phenanthrolineselenazole) (Ru-Se) has been synthesized and characterized. The G-quadruplex DNA-binding properties of the complex and its selenium ligand (Phen-Se) were evaluated by thermal denaturation study, polymerase chain reaction (PCR) stop assay, and telomerase repeat amplification protocol (TRAP). The results showed that the obtained complex could induce and stabilize G-quadruplex structure as well as exhibit potent inhibitory activity against telomerase. In vitro cytotoxicity studies showed that complex Ru-Se inhibited the cancer cell growth through apoptosis. However, the presence of the ligand Phen-Se did not appear to have a significant effect either on G-quadruplex binding or on biological activity. Furthermore, the cell migration assay and the tube formation assay also demonstrated that the complex Ru-Se significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, and tube formation. These findings indicate that the Ru-Se complex may be a potential telomerase inhibitor and a viable drug candidate in antiangiogenesis for anticancer therapies. Show less

The novel ligand (dmbip) 2-(4-N, N-dimethylbenzenamine)1H-imidazo[4, 5-f][1, 10]phenanthroline and its complexes [Ru(phen)2dmbip](2+) (1), [Ru(bpy)2dmbip](2+) (2), [Co(phen)2dmbip](3+) (3) and [Co(bpy)2dmbip](3+) (4) [where phen = 1, 10-phenanthroline, bpy = 2, 2'-bipyridine], have been synthesized and characterized by elemental analysis, IR, UV-Vis, (1)H NMR, (13)C NMR and Mass spectra. The DNA binding properties of the complexes were investigated by absorption, emission, quenching studies, light switch "on and off", salt dependent, sensor (cation and anion) studies, viscosity measurements, cyclic voltammetry, molecular modeling and docking studies. The four complexes were screened for Photo cleavage of pBR322 DNA, antimicrobial activity and cytotoxicity. The experimental results indicate that the four complexes can intercalate into DNA base pairs. The DNA-binding affinities of these complexes follow the order [Ru(phen)2dmbip](2+) > [Co(phen)2dmbip](3+) > [Ru(bpy)2dmbip](2+) > [Co(bpy)2dmbip](3+). Show less

Two new Ru(II) complexes, [Ru(bpy)2(FAMP)](ClO4)2 1 and 2, are synthesized and characterized by elemental analysis, electrospray mass spectrometry, and 1H nuclear magnetic resonance. The in vitro cytotoxicities and apoptosis-inducing properties of these complexes are extensively studied. Complexes 1 and 2 exhibit potent antiproliferative activities against a panel of human cancer cell lines. The cell cycle analysis shows that complexes 1 and 2 exhibit effective cell growth inhibition by triggering G0/G1 phase arrest and inducing apoptosis by mitochondrial dysfunction. The in vitro DNA binding properties of the two complexes are investigated by different spectrophotometric methods and viscosity measurements. Show less

The PTA N-alkyl derivatives (PTAC2H4OCOMe)X (1X: 1a, X = Br; 1b, X = I; 1c, X = PF6; 1d, X = BPh4), (PTACH2COOEt)X (2X: 2a, X = Br; 2b, X = Cl; 2c, X = PF6), and (PTACH2CH2COOEt)X (3X: 3a, X = Br; 3c, X = PF6), presenting all the functional groups of the natural cationic compounds acetylcholine or trimethylglycine combined with a P-donor site suitable for metal ion coordination, were prepared and characterized by NMR, ESI-MS, and elemental analysis. The X-ray crystal structures of 1d and 2c were determined. Ligands 1c, 2b, and 3c were coordinated to Pt(II) and Ru(II) to give the cationic complexes cis-[PtCl2(L)2]X2 and [RuCpCl(PPh3)(L)]X (L = 1, 2, 3, X = Cl or PF6) designed with a structure targeted for anticancer activity. The X-ray crystal structure of [CpRu(PPh3)(PTAC2H4OCOMe)Cl]PF6 (1cRu) was determined. The antiproliferative activity of the ligands and the complexes was evaluated on three human cancer cell lines. Show less