Two photoactivatable dicarbonyl ruthenium(II) complexes based on an amide-functionalised bipyridine scaffold (4-position) equipped with an alkyne functionality or a green-fluorescent BODIPY (boron-dipyrromethene) dye have been prepared and used to investigate their light-induced decarbonylation. UV/Vis, FTIR and 13 C NMR spectroscopies as well as gas chromatography and multivariate curve resolution alternating least-squares analysis (MCR-ALS) were used to elucidate the mechanism of the decarbonylation process. Release of the first CO molecule occurs very quickly, while release of the second CO molecule proceeds more slowly. In vitro studies using two cell lines A431 (human squamous carcinoma) and HEK293 (human embryonic kidney cells) have been carried out in order to characterise the anti-proliferative and anti-apoptotic activities. The BODIPY-labelled compound allows for monitoring the cellular uptake, showing fast internalisation kinetics and accumulation at the endoplasmic reticulum and mitochondria.

• Keywords
• anti-apoptotic activity, anti-proliferative, cellular localisation, photoCORM, ruthenium(II),
• MeSH
• 2,2'-Dipyridyl chemistry   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Carbon Monoxide chemistry   MeSH
• Prodrugs chemistry   radiation effects   MeSH
• Ruthenium chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 2,2'-Dipyridyl MeSH
• Carbon Monoxide MeSH
• Prodrugs MeSH
• Ruthenium MeSH

Ruthenium complexes currently represent a perspective subject of investigation in terms of potential anticancer therapeutics. Eight novel octahedral ruthenium(II) complexes are the subject of this article. Complexes contain 2,2'-bipyridine molecules and salicylates as ligands, differing in position and type of halogen substituent. The structure of the complexes was determined via X-ray structural analysis and NMR spectroscopy. All complexes were characterized by spectral methods-FTIR, UV-Vis, ESI-MS. Complexes show sufficient stability in solutions. Therefore, their biological properties were studied. Binding ability to BSA, interaction with DNA, as well as in vitro antiproliferative effects against MCF-7 and U-118MG cell lines were investigated. Several complexes showed anticancer effects against these cell lines.

• Keywords
• BSA, DNA, NSAID, Ruthenium(II), anticancer drugs, antiproliferative activity, crystal structure, medicinal inorganic chemistry, salicylate,
• MeSH
• Halogens MeSH
• Heterocyclic Compounds * MeSH
• Coordination Complexes * chemistry   MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents * chemistry   MeSH
• Ruthenium * pharmacology   chemistry   MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Halogens MeSH
• Heterocyclic Compounds * MeSH
• Coordination Complexes * MeSH
• Antineoplastic Agents * MeSH
• Ruthenium * MeSH

Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.

• Keywords
• 3D spheroids, Antimetastatic, Antiproliferative, Ruthenium, Vimentin,
• MeSH
• Cell Adhesion drug effects   MeSH
• Coordination Complexes * pharmacology   chemistry   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Metastasis prevention & control   drug therapy   MeSH
• Cell Line, Tumor MeSH
• Cell Movement * drug effects   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   therapeutic use   MeSH
• Ruthenium * chemistry   pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Coordination Complexes * MeSH
• Antineoplastic Agents * MeSH
• Ruthenium * MeSH

A series of four 2‑amino‑3‑cyano‑4‑(3/4‑pyridyl)‑4H‑benzo[h]chromenes 2a-d and their dichlorido(p‑cymene)ruthenium(II) complexes 3a-d were tested for antiproliferative, vascular-disruptive, anti-angiogenic and DNA-binding activity. The coordination of the 4‑pyridyl‑4H‑naphthopyrans 2 to ruthenium led to complexes with pleiotropic effects. Unlike the free ligands 2a-d, their ruthenium complexes 3a-d showed a significant affinity for DNA as demonstrated by electrophoretic mobility shift assays (EMSA) and ethidium bromide assays. Binding of 3a-d to calf thymus DNA proceeded about 10-times faster compared with cisplatin. Treatment of HT-29 colon carcinoma, 518A2 melanoma and MCF-7Topo breast cancer cells with 3a and 3b caused an accumulation of cells in the G2/M phase and an increase of the fraction of mitotic cells in the case of HT-29, due to alterations of the microtubule cytoskeleton as shown by immunofluorescence staining. Complexes 3b-c showed a dual effect on the vascular system. They suppressed angiogenesis in zebrafish embryos and they destroyed the vasculature of the chorioallantoic membrane (CAM) in fertilized chicken eggs. They also inhibited the vasculogenic mimicry, typical of U-87 glioblastoma cells in tube formation assays.

• Keywords
• (Arene)ruthenium(II) complexes, DNA binding, Naphthopyran, Vascular-disrupting agents (VDA), Zebrafish,
• MeSH
• HT29 Cells MeSH
• Chorioallantoic Membrane drug effects   MeSH
• Cisplatin pharmacology   MeSH
• Zebrafish MeSH
• DNA chemistry   MeSH
• Coordination Complexes chemistry   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Electrophoretic Mobility Shift Assay MeSH
• Ruthenium chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• calf thymus DNA MeSH Browser
• Cisplatin MeSH
• DNA MeSH
• Coordination Complexes MeSH
• Antineoplastic Agents MeSH
• Ruthenium MeSH

Two new luminescent ruthenium(II) polypyridyl complexes, [Ru(bpy)2 (tpt-phen)]Cl2 (1; bpy=2,2'-bipyridine, tpt-phen=triptycenyl-1,10-phenanthroline) and [Ru(phen)2 (tpt-phen)]Cl2 (2; phen=1,10-phenanthroline), have been developed as potential nonviral vectors for DNA delivery. Photophysical and electrochemical properties of the complexes have been investigated and corroborated with electronic structure calculations. DNA condensation by these complexes has been investigated by UV/Vis and emission spectroscopy, circular dichroism spectroscopy, atomic force microscopy, dynamic light scattering, confocal microscopy, and electrophoretic mobility studies. These complexes interact with DNA and efficiently condense DNA into globular nanoparticles that are taken up efficiently by HeLa cells. DNA cleavage inability and biocompatibility of complexes have been explored. Both complexes have good gene transfection abilities.

• Keywords
• DNA, electrochemistry, luminescence, photochemistry, ruthenium,
• MeSH
• Circular Dichroism MeSH
• DNA administration & dosage   chemistry   MeSH
• Genetic Vectors chemistry   MeSH
• HeLa Cells MeSH
• Coordination Complexes chemical synthesis   chemistry   MeSH
• Crystallography, X-Ray MeSH
• Quantum Theory * MeSH
• Humans MeSH
• Luminescence MeSH
• Microscopy, Atomic Force MeSH
• Molecular Structure MeSH
• Pyridines chemistry   MeSH
• Ruthenium chemistry   MeSH
• Gene Transfer Techniques instrumentation   MeSH
• Cell Survival MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA MeSH
• Coordination Complexes MeSH
• Pyridines MeSH
• Ruthenium MeSH

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEβ and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1β and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1β and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2β and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-β-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH3 and 4∙BH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1β, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the β anomer. However, Ru1β, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1β, inducing cell death by apoptosis.

• Keywords
• Anticancer metal complexes, Apoptosis, Carbohydrate complexes, Cell-cycle, Cytotoxicity, Glycoconjugation, Mitochondrial membrane potential, Phosphane ligand, Ruthenium(II) arene,
• MeSH
• Phosphines MeSH
• Coordination Complexes * chemistry   pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms * MeSH
• Antineoplastic Agents * chemistry   MeSH
• Ruthenium * chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Phosphines MeSH
• Coordination Complexes * MeSH
• Ligands MeSH
• phosphine MeSH Browser
• Antineoplastic Agents * MeSH
• Ruthenium * MeSH

We report DNA cleavage by ruthenium(II) arene anticancer complex [(η(6)-p-terp)Ru(II)(en)Cl](+) (p-terp=para-terphenyl, en=1,2-diaminoethane, complex 1) after its photoactivation by UVA and visible light, and the toxic effects of photoactivated 1 in cancer cells. It was shown in our previous work (T. Bugarcic et al., J. Med. Chem. 51 (2008) 5310-5319) that this complex exhibits promising toxic effects in several human tumor cell lines and concomitantly its DNA binding mode involves combined intercalative and monofunctional (coordination) binding modes. We demonstrate in the present work that when photoactivated by UVA or visible light, 1 efficiently photocleaves DNA, also in hypoxic media. Studies of the mechanism underlying DNA cleavage by photoactivated 1 reveal that the photocleavage reaction does not involve generation of reactive oxygen species (ROS), although contribution of singlet oxygen ((1)O2) to the DNA photocleavage process cannot be entirely excluded. Notably, the mechanism of DNA photocleavage by 1 appears to involve a direct modification of mainly those guanine residues to which 1 is coordinatively bound. As some tumors are oxygen-deficient and cytotoxic effects of photoactivated ruthenium compounds containing {Ru(η(6)-arene)}(2+) do not require the presence of oxygen, this class of ruthenium complexes may be considered potential candidate agents for improved photodynamic anticancer chemotherapy.

• Keywords
• Antitumor activity, Comet assay, DNA cleavage, Photodynamic chemotherapy, Phototoxicity, Ruthenium anticancer complex,
• MeSH
• DNA chemistry   MeSH
• Ethylenediamines chemistry   MeSH
• Photochemotherapy MeSH
• Cations, Divalent MeSH
• Coordination Complexes chemical synthesis   pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Organometallic Compounds chemical synthesis   pharmacology   MeSH
• Plasmids chemistry   MeSH
• Antineoplastic Agents chemical synthesis   pharmacology   MeSH
• Ruthenium chemistry   MeSH
• Base Sequence MeSH
• Singlet Oxygen chemistry   MeSH
• DNA Cleavage drug effects   radiation effects   MeSH
• Light MeSH
• Terphenyl Compounds chemistry   MeSH
• Cell Survival drug effects   radiation effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA MeSH
• Ethylenediamines MeSH
• ethylenediamine MeSH Browser
• Cations, Divalent MeSH
• Coordination Complexes MeSH
• Organometallic Compounds MeSH
• Antineoplastic Agents MeSH
• Ruthenium MeSH
• Singlet Oxygen MeSH
• Terphenyl Compounds MeSH

2-Amino-5,10-dihydro-5,10-dioxo-4(pyridine-3-yl)-4H-benzo[g]chromene-3-carbonitrile 5, a cytotoxic lawsone derivative, was reacted with [Ru(p-cymene)Cl2]2 to afford a new Ru(II) 'piano-stool' complex 6 which differed from its ligand 5 by a greater selectivity for highly invasive 518A2 melanoma cells over human dermal fibroblasts in MTT cytotoxicity assays, and by inducing senescence rather than apoptosis in the former. DNA is a likely cellular target of complex 6 as it bound, presumably non-covalently, to linear and circular double-stranded DNA in vitro and as ruthenium was found in the lysate of nuclei of treated 518A2 melanoma cells. It also caused a fivefold increase of reactive oxygen species in these cells, originating from a more persistent redox cycling as visualised by cyclic voltammetry.

• Keywords
• Anticancer agents, Lawsone, Melanoma, Naphthoquinone, Ruthenium(II) complex, Senescence,
• MeSH
• Cell Line MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• DNA, Circular metabolism   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction MeSH
• Cell Proliferation drug effects   genetics   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Ruthenium chemistry   MeSH
• Cellular Senescence drug effects   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Coordination Complexes MeSH
• DNA, Circular MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• Ruthenium MeSH

Reduction potentials of several M(2+/3+) (M = Ru, Os) octahedral complexes, namely, [M(H2O)6](2+/3+), [MCl6](4-/3-), [M(NH3)6](2+/3+), [M(en)3](2+/3+) [M(bipy)3](2+/3+), and [M(CN)6](4-/3-), were calculated using the CASSCF/CASPT2/CASSI and MRCI methods including spin-orbit coupling (SOC) by means of first-order quasi-degenerate perturbation theory. It was shown that the effect of SOC accounts for a systematic shift of approximately -70 mV in the reduction potentials of the studied ruthenium (II/III) complexes and an approximately -300 mV shift for the osmium(II/III) complexes. SOC splits the sixfold-degenerate (2)T(2g) ground electronic state (in ideal octahedral symmetry) of the M(3+) ions into the E((5/2)g) Kramers doublet and G((3/2)g) quartet, which were calculated to split by 1354-1573 cm(-1) in the Ru(3+) complexes and 4155-5061 cm(-1) in the Os(3+) complexes. It was demonstrated that this splitting represents the main contribution to the stabilization of the M(3+) ground state with respect to the closed-shell (1)A(1g) ground state in M(2+) systems. Moreover, it was shown that the accuracy of the calculated reduction potentials depends on the calculated solvation energies of both the oxidized and reduced forms. For smaller ligands, it involves explicit inclusion of the second solvation sphere into the calculations, whereas implicit solvation models yield results of sufficient accuracy for complexes with larger ligands. In such cases (e.g., [M(bipy)3](2+/3+) and its derivatives), very good agreement between the calculated (SOC-corrected) values of the reduction potentials and the available experimental values was obtained. These results led us to the conclusion that especially for Os(2+/3+) complexes, inclusion of SOC is necessary to avoid systematic errors of approximately 300 mV in the calculated reduction potentials.

• MeSH
• Models, Chemical MeSH
• Quantum Theory * MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Organometallic Compounds chemistry   MeSH
• Osmium chemistry   MeSH
• Oxidation-Reduction MeSH
• Computer Simulation MeSH
• Ruthenium chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Organometallic Compounds MeSH
• Osmium MeSH
• Ruthenium MeSH

While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2-9 in 77-99% yields. Products 2-9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1, 7, and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake.

• MeSH
• Homeostasis MeSH
• Coordination Complexes * pharmacology   MeSH
• Humans MeSH
• Mitochondria MeSH
• Cell Line, Tumor MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * pharmacology   therapeutic use   MeSH
• Ruthenium * pharmacology   MeSH
• Calcium MeSH
• Water MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Coordination Complexes * MeSH
• Antineoplastic Agents * MeSH
• Ruthenium * MeSH
• Calcium MeSH
• Water MeSH