Novel Organoruthenium(II) β‑Diketonates as Catalysts for Ortho Arylation via C–H Activation

Five different fluorinated β-diketone ligands in the presence of sodium methoxide easily react with the organoruthenium precursor [(η⁶-<i>p</i>-cymene)­Ru­(μ-Cl)­Cl]₂, generating neutral complexes <b>1</b>–<b>5</b> with typical “piano-stool” geometry. All synthesized compounds were characterized by multinuclear NMR, X-ray diffraction, and other standard physicochemical methods. These isolated organoruthenium­(II) complexes are air-, moisture-, and UV-stable compounds and were tested for catalytic activity. It was found that these compounds are ready to use catalysts, which are efficient for direct arylation of 2-phenylpyridine. With the use of 4-bromoacetophenone as arylating reagent, these complexes show enhanced selectivity for monoarylated products. All reagents are commercially available and relatively inexpensive, which makes these catalysts generally available

Novel Organoruthenium(II) β‑Diketonates as Catalysts for Ortho Arylation via C–H Activation

Five different fluorinated β-diketone ligands in the presence of sodium methoxide easily react with the organoruthenium precursor [(η⁶-<i>p</i>-cymene)­Ru­(μ-Cl)­Cl]₂, generating neutral complexes <b>1</b>–<b>5</b> with typical “piano-stool” geometry. All synthesized compounds were characterized by multinuclear NMR, X-ray diffraction, and other standard physicochemical methods. These isolated organoruthenium­(II) complexes are air-, moisture-, and UV-stable compounds and were tested for catalytic activity. It was found that these compounds are ready to use catalysts, which are efficient for direct arylation of 2-phenylpyridine. With the use of 4-bromoacetophenone as arylating reagent, these complexes show enhanced selectivity for monoarylated products. All reagents are commercially available and relatively inexpensive, which makes these catalysts generally available

Novel Organoruthenium(II) β‑Diketonates as Catalysts for Ortho Arylation via C–H Activation

Five different fluorinated β-diketone ligands in the presence of sodium methoxide easily react with the organoruthenium precursor [(η⁶-<i>p</i>-cymene)­Ru­(μ-Cl)­Cl]₂, generating neutral complexes <b>1</b>–<b>5</b> with typical “piano-stool” geometry. All synthesized compounds were characterized by multinuclear NMR, X-ray diffraction, and other standard physicochemical methods. These isolated organoruthenium­(II) complexes are air-, moisture-, and UV-stable compounds and were tested for catalytic activity. It was found that these compounds are ready to use catalysts, which are efficient for direct arylation of 2-phenylpyridine. With the use of 4-bromoacetophenone as arylating reagent, these complexes show enhanced selectivity for monoarylated products. All reagents are commercially available and relatively inexpensive, which makes these catalysts generally available

Synthesis and Biological Evaluation of Organoruthenium Complexes with Azole Antifungal Agents. First Crystal Structure of a Tioconazole Metal Complex

Nine organoruthenium complexes with azole antifungal agents (L) clotrimazole (<b>ctz</b>), tioconazole (<b>tcz</b>), and miconazole (<b>mcz</b>) with the general formulas [(η⁶-<i>p</i>-cymene)­RuCl₂(L)], [(η⁶-<i>p</i>-cymene)­RuCl­(L)₂]­Cl, and [(η⁶-<i>p</i>-cymene)­Ru­(L)₃]­(PF₆)₂ were prepared and characterized by NMR, HRMS, IR, UV–vis, and X-ray crystallography. Herein, we report the first crystal structure of a tioconazole metal complex as well as the structure of the tioconazole ligand itself and the bis-clotrimazole complex as a hexafluorophosphate salt. The complexes possess a pseudooctahedral geometry typical for organoruthenium­(II) compounds where half of the coordination sites are occupied by the π-bonded arene ligand <i>p</i>-cymene while the remaining sites are occupied by either the chlorido ligands and/or the azole ligands. The stability of the compounds in dmso solution was studied by NMR spectroscopy. The biological activity of all nine complexes and the ruthenium precursor against the fungus <i>Culvularia lunata</i> was evaluated. The complexes showed antifungal activity at low millimolar concentrations, where the activity decreased with the increasing number of ligands. However at 0.5 mM concentrations all tris-azole complexes statistically significantly reduced the radial growth rate, and also at 0.01 mM concentrations the monoazole complexes showed statistically significant effects. <b>Mcz</b> and its complexes were also tested against the human parasite <i>Schistosoma mansoni</i> and revealed schistocidal activity at 10–100 μg/mL in vitro

New Water-Soluble Ruthenium(II) Terpyridine Complexes for Anticancer Activity: Synthesis, Characterization, Activation Kinetics, and Interaction with Guanine Derivatives

With the aim of assessing whether ruthenium­(II) compounds with meridional geometry might be utilized as potential antitumor agents, a series of new, water-soluble, monofunctional ruthenium­(II) complexes of the general formula <i>mer</i>-[Ru­(L₃)­(N-N)­X]­[Y]_<i>n</i> (where L₃ = 2,2′:6′,2″-terpyridine (tpy) or 4′-chloro-2,2′:6′,2″-terpyridine (Cl-tpy), N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach), or 2,2′-bipyridine (bpy); X = Cl or dmso-<i>S</i>; Y = Cl, PF₆, or CF₃SO₃; <i>n</i> = 1 or 2, depending on the nature of X) were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and for three of them, i.e., [Ru­(Cl-tpy)­(bpy)­Cl]­[Cl] (<b>3</b>_<b>Cl</b>), [Ru­(Cl-tpy)­(en)­(dmso-<i>S</i>)]­[Y]₂ [Y = PF₆ (<b>6</b>_<b>PF₆</b>), CF₃SO₃ (<b>6</b>_<b>OTf</b>)] and [Ru­(Cl-tpy)­(bpy)­(dmso-<i>S</i>)]­[CF₃SO₃]₂ (<b>8</b>_<b>OTf</b>), the X-ray structure was also determined. The new terpyridine complexes, with the exception of <b>8</b>, are well soluble in water (>25 mg/mL). ¹H and ³¹P NMR spectroscopy studies performed on the three selected complexes [Ru­(Cl-tpy)­(N-N)­Cl]⁺ [N-N = en (<b>1</b>), dach (<b>2</b>), and bpy (<b>3</b>)] demonstrated that, after hydrolysis of the Cl ligand, they are capable of interacting with guanine derivatives [i.e., 9-methylguanine (9MeG) or guanosine-5′-monophosphate (5′-GMP)] through N7, forming monofunctional adducts with rates and extents that depend strongly on the nature of N-N: <b>1</b> ≈ <b>2</b> ≫ <b>3</b>. In addition, compound <b>1</b> shows high selectivity toward 5′-GMP compared to adenosine-5′-monophosphate (5′-AMP), in a competition experiment. Quantitative kinetic investigations on <b>1</b> and <b>2</b> were performed by means of UV/visible spectroscopy. Overall, the complexes with bidentate aliphatic diamines proved to be superior to those with bpy in terms of solubility and reactivity (i.e., release of Cl^– and capability to bind guanine derivatives). Contrary to the chlorido compounds, the corresponding dmso derivatives proved to be inert (viz., they do not release the monodentate ligand) in aqueous media

New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]­aneS₃)­(dmso-κS)­(quinolonato-κ^<i>2</i>O,O)]­(PF₆), containing the quinolones levofloxacin (<b>1</b>), nalidixic acid (<b>2</b>), oxolinic acid (<b>3</b>), and cinoxacin (<b>4</b>), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of <b>4</b>. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV–vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes <b>1</b>–<b>4</b>. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound <b>4</b>, which also shows the most pronounced rate of hydrolysis. Compounds <b>2</b> and <b>4</b> also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex <b>2</b> displayed moderate cytotoxicity when tested on the HeLa cell line

New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]­aneS₃)­(dmso-κS)­(quinolonato-κ^<i>2</i>O,O)]­(PF₆), containing the quinolones levofloxacin (<b>1</b>), nalidixic acid (<b>2</b>), oxolinic acid (<b>3</b>), and cinoxacin (<b>4</b>), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of <b>4</b>. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV–vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes <b>1</b>–<b>4</b>. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound <b>4</b>, which also shows the most pronounced rate of hydrolysis. Compounds <b>2</b> and <b>4</b> also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex <b>2</b> displayed moderate cytotoxicity when tested on the HeLa cell line

New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]­aneS₃)­(dmso-κS)­(quinolonato-κ^<i>2</i>O,O)]­(PF₆), containing the quinolones levofloxacin (<b>1</b>), nalidixic acid (<b>2</b>), oxolinic acid (<b>3</b>), and cinoxacin (<b>4</b>), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of <b>4</b>. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV–vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes <b>1</b>–<b>4</b>. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound <b>4</b>, which also shows the most pronounced rate of hydrolysis. Compounds <b>2</b> and <b>4</b> also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex <b>2</b> displayed moderate cytotoxicity when tested on the HeLa cell line

Structure-Related Mode-of-Action Differences of Anticancer Organoruthenium Complexes with β‑Diketonates

A series of organoruthenium­(II) chlorido complexes with fluorinated O,O-ligands [(η⁶-<i>p</i>-cymene)­Ru­(F₃C-acac-Ar)­Cl] (<b>1a</b>–<b>6a</b>) and their respective 1,3,5-triaza-7-phosphaadamantane (pta) derivatives [(η⁶-<i>p</i>-cymene)­Ru­(F₃C-acac-Ar)­pta]­PF₆ (<b>1b</b>–<b>6b</b>) were synthesized and fully characterized in both solution and solid state. All complexes were inactive against nonmalignant keratinocytes but displayed variable activity against cancer cell models (ovarian, osteosarcoma). Compounds with a ligand containing the 4-chlorophenyl substituent (<b>6a</b> and <b>6b</b>) exhibited the strongest anticancer effects. Despite a marginally lower cellular Ru accumulation compared to the chlorido complexes, pta analogues showed higher activity especially in the osteosarcoma model. Reduction of glutathione levels by buthionine sulfoximine (BSO) significantly enhanced the activity of all compounds with the most pronounced effects being observed for the pta series resulting in IC₅₀ values down to the nanomolar range. While all chlorido complexes potently induce reactive oxygen species, DNA damage, and apoptosis, the respective pta compounds widely lacked ROS production but blocked cell cycle progression in G0/G1 phase

Physicochemical Studies and Anticancer Potency of Ruthenium η⁶-<i>p</i>-Cymene Complexes Containing Antibacterial Quinolones

With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (<b>2</b>) and cinoxacin (<b>3</b>) were synthesized, and their physicochemical properties were compared to those of chlorido(η⁶-<i>p</i>-cymene)(ofloxacinato-κ²<i>O</i>,<i>O</i>)ruthenium(II) (<b>1</b>). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. <b>2</b> and <b>3</b> are significantly more stable than <b>1</b> and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)₃Ru(cym)]⁺ species (cym = η⁶-<i>p</i>-cymene). In the presence of human serum albumin <b>1</b>−<b>3</b> form adducts with this transport protein within 20 min of incubation. With guanosine 5′-monophosphate (5′-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for <b>1</b> in CH1 ovarian cancer cells, whereas <b>2</b> and <b>3</b> turned out to be inactive