Search Results (25)

Two diruthenium(II,II) naphthyridine complexes coordinated with 4-trifluoromethylbenzoate (O₂CPh-4-CF₃) and 3,5-bis(trifluoromethyl)benzoate (O₂CPh-3,5-diCF₃) ligands, formulated as [Ru₂(npc)₂(O₂CPh-4-CF₃)₂] (4; npc = 1,8-naphthyridine-2-carboxylate) and [Ru₂(npc)₂(O₂CPh-3,5-diCF₃)₂] (5), respectively, were synthesized and structurally characterized. Single-crystal X-ray diffraction analysis revealed that both 4 and 5 form a direct metal–metal bond between the two Ru ions (2.2893(8) and 2.2896(7) Å, respectively) and adopt a paddlewheel-type structure in which two npc and two trifluoromethyl-substituted benzoate ligands are coordinated to a Ru₂⁴⁺ core with a cis-2:2 arrangement. The temperature dependence of the magnetic susceptibility measurements of 4 and 5 exhibited very large zero-field splitting (D = 242 and 246 cm⁻¹, respectively) of the triplet ground state of the Ru₂⁴⁺ core, similar to that of [Ru₂(npc)₂(O₂CPh)₂] (3; D = 238 cm⁻¹). Owing to the effects of the trifluoromethyl substituents, compared with 3, 4 and 5 showed (i) a significant blue shift of the absorption bands in the visible region and (ii) a positive shift of the redox potentials, with both shifts becoming more pronounced as the number of trifluoromethyl substituents increased. These experimental results are in good agreement with the electronic structure results obtained from density functional theory calculations. Full article

A ligand exchange reaction between [Ru₂(npc)₂(O₂CMe)₂] (1; npc = 1,8-naphthyridine-2-carboxylate) and trifluoroacetic acid yielded the diruthenium naphthyridine complex with two trifluoroacetate ligands, [Ru₂(npc)₂(O₂CCF₃)₂] (2), which was structurally characterized by electrospray ionization mass spectrometry, elemental analysis, infrared spectrum, and synchrotron single-crystal X-ray diffraction. The crystal structure of 2 adopts a paddlewheel-type structure in which two npc and two O₂CCF₃ ligands are coordinated in a cis-2:2 arrangement around the Ru₂ core. The temperature-dependent magnetic susceptibility measurements indicated that 2 has (i) an S = 1 spin state for the Ru₂⁴⁺ core and (ii) a large D value of 243 cm⁻¹; characteristic of paddlewheel-type Ru₂ complexes. The cyclic voltammetry measurements indicated that 2 exhibited one reversible oxidation wave (E_1/2 = 0.72 V vs. SCE) and two reduction waves (E_1/2 = −0.67 and −1.10 V vs. SCE); which were clearly positively shifted when compared with those of 1. Additionally, the absorption spectrum of 2 displayed intense absorption bands in the visible region; attributed to metal-to-ligand charge transfer from the Ru₂ core to the npc ligands; which were blue-shifted by approximately 70–100 nm when compared with those of 1. These distinct shifts in redox potentials and absorption bands originated from the strong electron-withdrawing effect of the O₂CCF₃ ligands in 2. Full article

We conducted a joint synthetic, spectroscopic and computational study to explore the reactivity towards cyanide (from Bu₄NCN) of a series of dinuclear complexes based on the M₂Cp₂(CO)₃ scaffold (M = Fe, Ru; Cp = η⁵-C₅H₅), namely [M₂Cp₂(CO)₂(µ-CO){µ,η¹:η²-CH=C=CMe₂}]BF₄ (1Fe-Ru), [Ru₂Cp₂(CO)₂(µ-CO){µ,η¹:η²-C(Ph)=CHPh}]BF₄ (2Ru) and [M₂Cp₂(CO)₂(µ-CO){µ-CN(Me)(R)}]CF₃SO₃ (3Fe-Ru). While the reaction of 1Fe with Bu₄NCN resulted in prevalent allenyl deprotonation, preliminary CO-NCMe substitution in 1Ru enabled cyanide addition to both the allenyl ligand (resulting in the formation of a h¹:h²-allene derivative, 5A) and the two metal centers (affording 5B1 and 5B2). The mixture of 5B1-2 was rapidly converted into 5A in heptane solution at 100 °C, with 5A being isolated with a total yield of 60%. Following carbonyl-chloride substitution in 2Ru, CN⁻ was incorporated as a terminal ligand upon Cl⁻ displacement, to give the alkenyl complex 6 (84%). The reactivity of 3Fe and 3Ru is strongly influenced by both the metal element, M, and the aminocarbyne substituent, R. Thus, 7aRu was obtained with a 74% yield from cyanide attack on the carbyne in 3aRu (R = Cy, cyclohexyl), whereas the reaction involving the diiron counterpart 3aFe yielded an unclean mixture of the metastable 7aFe and the CO/CN⁻ substitution product 8aFe. The cyano-alkylidene complexes 7aRu (R = Cy) and 7bFe (R = Me) underwent CO loss and carbene to carbyne conversion in isopropanol at 60–80 °C, giving 8aRu (48%) and 8bFe (71%), respectively. The novel compounds 5A, 5B1-2, 6 and 7aRu were characterized by IR and NMR spectroscopy, with the structure of 7aRu further elucidated by single crystal X-ray diffraction analysis. Additionally, the DFT-optimized structures of potential isomers of 5A, 5B1-2 and 6 were calculated. Full article

Metallodrugs are an important group of medicinal agents used for the treatment of various diseases ranging from cancers to viral, bacterial, and parasitic diseases. Their distinctive features include the availability of a metal centre, redox activity, as well as the ability to multitarget. Diruthenium paddlewheel complexes are an intensely developing group of metal scaffolds, which can securely coordinate bidentate xenobiotics and transport them to target tissues, releasing them by means of substitution reactions with biomolecular nucleophiles. It is of the utmost importance to gain a complete comprehension of which chemical reactions happen with them in physiological milieu to design novel drugs based on these bimetallic scaffolds. This review presents the data obtained in experiments and calculations, which clarify the chemistry these complexes undergo once administered in the proteic environment. This study demonstrates how diruthenium paddlewheel complexes may indeed embody a new paradigm in the design of metal-based drugs of dual-action by presenting and discussing the protein metalation by these complexes. Full article

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC ‘click’ (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions, and there in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) and in non-infected human foreskin fibroblasts, HFF, was determined at 0.1 and 1 µM. When evaluated at 1 µM, seven diruthenium-carbohydrate conjugates strongly impaired parasite proliferation by >90%, while HFF viability was retained at 50% or more, and they were further subjected to the half-maximal inhibitory concentration (IC₅₀) measurement on T. gondii β-gal. Results revealed that the biological activity of the hybrids was influenced both by the nature of the carbohydrate (glucose vs. galactose) appended on ruthenium complex and the type/length of the linker between the two units. 23 and 26, two galactose-based diruthenium conjugates, exhibited low IC₅₀ values and reduced effect on HFF viability when applied at 2.5 µM (23: IC₅₀ = 0.032 µM/HFF viability 92% and 26: IC₅₀ = 0.153 µM/HFF viability 97%). Remarkably, compounds 23 and 26 performed significantly better than the corresponding carbohydrate non-modified diruthenium complexes, showing that this type of conjugates are a promising approach for obtaining new antiparasitic compounds with reduced toxicity. Full article

Aiming toward compounds with improved anti-Toxoplasma activity by exploiting the parasite auxotrophies, a library of nucleobase-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates was synthesized and evaluated. Structural features such as the type of nucleobase and linking unit were progressively modified. For comparison, diruthenium hybrids with other type of molecules were also synthesized and assessed. A total of 37 compounds (diruthenium conjugates and intermediates) were evaluated in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. Twenty compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal half maximal inhibitory concentration determination (IC₅₀) and their toxicity for HFF was assessed at 2.5 µM. Two promising compounds were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC₅₀ values of 0.059 and 0.111 µM respectively, significantly lower compared to pyrimethamine standard (IC₅₀ = 0.326 µM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 µM and are candidates for potential treatment options in a suitable in vivo model. Full article

The poor water-solubility and instability of Ru(II) carbonyl complex hamper the therapeutic application as CO releasing materials (CO-RMs). To enhance the hydrophilicity and bio-utility of CO, a robust Ru(I) carbonyl sawhorse skeleton was grafted with water-soluble PEGylated sidearm. In this case, 12 PEGylated sawhorse Ru₂(CO)₄ complexes were prepared with satisfactory yields and characterized by IR and ¹H- and ¹³C- NMR. X-ray diffraction analysis of CO-RM 8, 13 and 14 revealed the featured diruthenium sawhorse skeleton and PEGylated axial ligands. The flask-shaking method measures the water-solubility of CO-RMs, indicating that both bridging carboxylate ligands and PEGlyated axial ligands regulate the hydrophilicity of these CO-RMs. Under photolysis conditions, CO-RM 4–13 sustainable released therapeutic amounts of CO in the myoglobin assay. The correlation of the CO release kinetics and hydrophilicity of CO-RMs demonstrated that the more hydrophilic CO-RM released CO faster. The biological test found that the low cytotoxic CO-RM 4 showed a specific anticancer activity toward HT-29 tumour cells. Full article

Heterometallic complexes of tetrakis(µ-carboxylato)diruthenium(II,III) with tetracyanidoaurate(III) [Ru₂(RCOO)₄Au(CN)₄]_n (R = CH₃ (1), C₂H₅ (2), i-C₃H₇ (3), and t-C₄H₉ (4)) were synthesized and characterized by C,H,N-elemental analysis and infrared spectroscopy and diffuse reflectance spectroscopy. The molecular structures were determined by a single-crystal X-ray diffraction method. A polymeric arrangement with the Ru₂(RCOO)₄⁺ units alternately linked by Au(CN)₄⁻ units is formed in these complexes. The trans-bridging mode of the Au(CN)₄⁻ unit for connecting the two Ru₂(RCOO)₄⁺ units was observed for 1 and 4, while the cis-bridging mode of the Au(CN)₄⁻ unit was observed for 2 and 3. Magnetic susceptibility data with variable temperature were modeled with a zero-field splitting model (D = 75 cm⁻¹) and the presence of weak antiferromagnetic coupling between the Ru^IIRu^III units (zJ = −0.15~−0.10 cm⁻¹) was estimated. N₂-adsorption isotherms showed Type II curves with S_BET of 0.728–2.91 m² g⁻¹. Full article

Conventional heating and solvothermal synthetic methods (with or without microwave activation) have been used to study the reaction of o-, m- and p-methoxybenzoic acid with [Ru₂Cl(μ-O₂CMe)₄]. The tetrasubstituted series [Ru₂Cl(µ-O₂CC₆H₄-R)₄], with R = o-OMe, m-OMe and p-OMe, has been prepared by the three procedures. Depending on the synthetic method and the experimental conditions, three compounds have been isolated (1a, 1b, 1c) with the o-methoxybenzoate ligand. However, with the m- and p-methoxybenzoate ligands, only the complexes 2 and 3 have been obtained, respectively. Compound 1a, with stoichiometry [Ru₂Cl(µ-O₂CC₆H₄-o-OMe)₄]_n, shows a polymeric structure with the chloride ions bridging the diruthenium units to form linear chains. Compounds 2 and 3, with the same stoichiometry, predictably form zig-zag chains in accordance with their insolubility and their magnetic measurements. Compound 1b, [Ru₂Cl(µ-O₂CC₆H₄-o-OMe)₄(EtOH)], is a discrete molecular species with a chloride ion and one ethanol molecule occupying the axial positions of the dimetallic unit. Compound 1c is a cation-anion complex, [Ru₂(µ-O₂CC₆H₄-o-OMe)₄(MeOH)₂][Ru₂Cl₂(µ-O₂CC₆H₄-o-OMe)₄]. The cationic complex has two solvent molecules at the axial positions whereas the anionic complex has two chloride ligands at these positions. Complexes have been characterized by elemental analyses, mass spectrometry and IR and UV-vis-NIR spectroscopies. A magnetic study of complexes 1a, 1b, 2 and 3 have also been carried out. The crystal structure of compounds 1b and 1c have been solved by single X-ray crystal methods. Full article

Careful optimization of the reaction conditions provided access to the particularly small tetraruthenium macrocycle ²Ru₂Ph-Croc, which is composed out of two redox-active divinylphenylene-bridged diruthenium entities {Ru}-1,4-CH=CH-C₆H₄-CH=CH-{Ru} (Ru₂Ph; {Ru} = Ru(CO)Cl(PⁱPr₃)₂) and two likewise redox-active and potentially non-innocent croconate linkers. According to single X-ray diffraction analysis, the central cavity of ²Ru₂Ph-Croc is shielded by the bulky PⁱPr₃ ligands, which come into close contact. Cyclic voltammetry revealed two pairs of split anodic waves in the weakly ion pairing CH₂Cl₂/NBu₄BAr^F₂₄ (BAr^F₂₄ = [B{C₆H₃(CF₃)₂-3,5}₄]⁻ electrolyte, while the third and fourth waves fall together in CH₂Cl₂/NBu₄PF₆. The various oxidized forms were electrogenerated and scrutinized by IR and UV/Vis/NIR spectroscopy. This allowed us to assign the individual oxidations to the metal-organic Ru₂Ph entities within ²Ru₂Ph-Croc, while the croconate ligands remain largely uninvolved. The lack of specific NIR bands that could be assigned to intervalence charge transfer (IVCT) in the mono- and trications indicates that these mixed-valent species are strictly charge-localized. ²Ru₂Ph-Croc is hence an exemplary case, where stepwise IR band shifts and quite sizable redox splittings between consecutive one-electron oxidations would, on first sight, point to electronic coupling, but are exclusively due to electrostatic and inductive effects. This makes ²Ru₂Ph-Croc a true “pretender”. Full article

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC₅₀ (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity. Full article

Hypoxanthine (hpx) is an important molecule for both biochemistry research and biomedical applications. It is involved in several biological processes associated to energy and purine metabolism and has been proposed as a biomarker for a variety of disease states. Consequently, the discovery and development of systems suitable for the detection of hypoxanthine is pretty appealing in this research field. Thus, we have obtained a stable diruthenium (III) compound in its dehydrated and hydrated forms with formula [{Ru(µ-Cl)(µ-hpx)}₂Cl₄] (1a) and [{Ru(µ-Cl)(µ-hpx)}₂Cl₄]·2H₂O (1b), respectively. This purine-based diruthenium(III) system was prepared from two very different starting materials, namely, inosine and azathioprine, the latter being an immunosuppressive drug. Remarkably, it was observed that an unusual azathioprine hydrolysis occurs in the presence of ruthenium, thus generating hypoxanthine instead of the expected 6-mercaptopurine antimetabolite, so that the hpx molecule is linked to two ruthenium(III) ions. 1a and 1b were characterized through IR, SEM, powder and single-crystal X-ray Diffraction and Cyclic Voltammetry (CV). The electrochemical studies allowed us to detect the hpx molecule when coordinated to ruthenium in the reported compound. The grade of sensitivity, repeatability and stability reached by this diruthenium system make it potentially useful and could provide a first step to develop new sensor devices suitable to detect hypoxanthine. Full article

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC₅₀ values ranging from 90 to 539 nM, and seven derivatives displayed IC₅₀ values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC₅₀ values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC₅₀ values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6–10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11–14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation. Full article

Two chiral face-rotating metalla-assembled polyhedra were constructed upon self-assembling achiral components, i.e., a tritopic ligand based on a truxene core (10,15-dihydro-5H-diindeno[1,2-a;1′,2′-c]fluorene) and two different hydroxyquinonato–bridged diruthenium complexes. Both polyhedra were characterized in solution as well as in the solid state by X-ray crystallography. In both cases, the self-sorting process leading to only two homo-chiral enantiomers was governed by non-covalent interactions between both truxene units that faced each other. Full article

The trithiolato bridged diruthenium complex DiRu-1 [(p-MeC₆H₄ⁱPr)₂Ru₂(SC₆H₄-p-Bu^t)₃]⁺ is highly cytotoxic against various cancer cell lines, but its exact mode of action remains unknown. The present ¹H HR-MAS NMR-based metabolomic study was performed on ovarian cancer cell line A2780, on its cis-Pt resistant variant A2780cisR, and on the cell line HEK-293 treated with 0.03 µM and 0.015 µM of DiRu-1 corresponding to full and half IC₅₀ doses, respectively, to investigate the mode of action of this ruthenium complex. The resulting changes in the metabolic profile of the cell lines were studied using HR-MAS NMR of cell lysates and a subsequent statistical analysis. We show that DiRu-1 in a 0.03 µM dose has significant impact on the levels of a number of metabolites, such as glutamine, glutamate, glutathione, cysteine, lipid, creatine, lactate, and acetate, especially pronounced in the A2780cisR cell line. The IC₅₀/2 dose shows some significant changes, but full IC₅₀ appears to be necessary to observe the full effect. Overall, the metabolic changes observed suggest that redox homeostasis, the Warburg effect, and the lipid metabolism are affected by DiRu-1. Full article