Water-soluble Ru Research Articles

Design and Anticancer Properties of New Water-Soluble Ruthenium-Cyclopentadienyl Complexes.

Ruthenium complexes are emerging as one of the most promising classes of complexes for cancer therapy. However, their limited aqueous solubility may be the major limitation to their potential clinical application. In view and to contribute to the progress of this field, eight new water-soluble Ru(II) organometallic complexes of general formula [RuCp(mTPPMS)n(L)] [CF3SO3], where mTPPMS = diphenylphosphane-benzene-3-sulfonate, for n = 2, L is an imidazole-based ligand (imidazole, 1-benzylimidazole, 1-butylimidazole, (1-(3-aminopropyl)imidazole), and (1-(4-methoxyphenyl)imidazole)), and for n = 1, L is a bidentate heteroaromatic ligand (2-benzoylpyridine, (di(2-pyridyl)ketone), and (1,2-(2-pyridyl)benzo-[b]thiophene)) were synthesized and characterized. The new complexes were fully characterized by NMR, FT-IR, UV–vis., ESI-HRMS, and cyclic voltammetry, which confirmed all the proposed molecular structures. The antiproliferative potential of the new Ru(II) complexes was evaluated on MDAMB231 breast adenocarcinoma, A2780 ovarian carcinoma, and HT29 colorectal adenocarcinoma cell lines, showing micromolar (MDAMB231 and HT29) and submicromolar (A2780) IC50 values. The interaction of complex 6 with human serum albumin (HSA) and fatty-acid-free human serum albumin (HSAfaf) was evaluated by fluorescence spectroscopy techniques, and the results revealed that the ruthenium complex strongly quenches the intrinsic fluorescence of albumin in both cases.

Testing diverse strategies for ruthenium catalyst removal after aqueous homogeneous olefin metathesis

Traditionally, olefin metathesis (OM) is carried out in organic solvents such as dichloromethane or toluene. Due to the development of water-resistant or even water-soluble ruthenium catalysts in the last two decades, considerable progress on OM in aqueous media has been made. However, the removal of ruthenium from the product of OM reactions performed in water remains a substantial challenge. In the present work, selected approaches to purify the reaction mixtures after aqueous homogeneous olefin metathesis (AHOM) reactions have been probed to address this shortcoming. It was found that elimination of a water-soluble Ru catalyst after AHOM conducted in neat water can be achieved via addition of thiocyanate ions (with or without support of charcoal additive). The developed purification method can make the aqueous metathesis methodology more practical, allowing easier separation of a spent water-soluble catalyst from the water-soluble metathesis products. Unfortunately, this methodology did not provide satisfactory results in the case of AHOM reactions performed in water/alcohol mixtures. To allow separation of a Ru catalyst in the latter case, a method utilizing a stimuli-responsive polymer was tested, leading however to limited success.

N-heterocyclic Carbene Containing Homogeneous Ru Catalyst for Aqueous Atom Transfer Radical Polymerization of Water-soluble Vinyl Monomers

This report presents aqueous atom transfer radical polymerization (ATRP) of commonly used acrylate monomers in the presence of N-Heterocyclic carbene (NHC) containing homogeneous Ru catalyst in neat water. The newly synthesized Ru catalyst includes NHC, which possesses poly(ethylene glycol) (PEG) as a water-soluble component and benzylidene. The water-soluble Ru catalyst enables the polymerization of acrylamide, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), and PEG methyl ether methacrylate. Polymerization with this new catalyst displayed typical ATRP behavior such as a low PDI, a direct linear relationship between molecular weight and conversion, and first-order kinetics. The polySBMA (Mn 335.5 kDa and PDI 1.66) was prepared with 91% conversion at 6 h of reaction time with 0.05 mol% catalyst loading in neat water ([catalyst]:[monomer] = 1:2000 at 80 °C). Without the Ru catalyst, the thermally initiated polymerization displayed uncontrolled polymerization (e.g., non-linear kinetics, high PDI, and too fast or slow polymerizations). The Ru catalyst also demonstrated ATRP of the PEG methyl ether methacrylate in an organic solvent, acetonitrile. More detailed studies of initiator amount, solvent concentration, and catalyst amount effects were performed. In turn, the new ATRP will add prominent value to the polymer science field as an initial example of Ru-benzylidene catalyzed ATRP in neat water. Additionally, this will promote various applications of environmentally benign polymerization as well as applications in the biomedical field with high-cost efficiency.

Synthesis and catalytic applications of Ru(II)-phosphaurotropine complexes with the use of simple water-soluble Ru(II)-precursors

1,3,5-Triaza-7-phosphaadamantane (pta, phosphaurotropine) played a special role in the development of aqueous organometallic chemistry and catalysis. The main reason is in its easy synthesis, oxidation stability, versatile possibilities of functionalization, and high solubility not only in water but also in several common organic solvents. Such favourable solubility behaviour allowed straightforward synthesis of pta-containing transition metal complexes from simple, inexpensive, often commercial starting materials. A further advantage of pta and its complexes is in their pronounced tendency to crystallize which allowed determination of solid-state structures of a great number of such compounds. This review covers synthetic procedures of ruthenium(II)-complexes with pta, and N-alkyl-pta derivatives as ligands, as well as their most important reactions in aqueous systems. Ru(II)-pta complexes were employed as catalysts in several important aqueous-phase processes such as selective hydrogenation and transfer hydrogenation of aldehydes, hydration of nitriles, and redox isomerization of allylic alcohols. Hydrogenation of carbon dioxide/bicarbonate and dehydrogenation of formic acid/aqueous formate were also studied with various Ru(II)-complexes of phosphaurotropines. Altogether the results described in this review made a significant positive impact on the development of green chemical processes.

Ru(ii)- and Ru(iv)-dmso complexes catalyze efficient and selective aqueous-phase nitrile hydration reactions under mild conditions

Synthesis and characterization of new water-soluble Ru(ii)- and Ru(iv)-dmso complexes are reported which show good efficiency and selectivity for aqueous-phase nitrile hydration at 60 °C in air. Best performance is achieved using complex [RuCl2(dmso)3(NH3)]·PF6·Cl (3).

Functionalisation of gold nanoparticles with ruthenium(II) polypyridyl complexes for their application in cellular imaging.

Two new dinuclear Ru(ii) polypyridyl complexes containing an alkyl disulphide functionalised bipyridine-based ligand and either 1,10-phenanthroline (phen) or 1,4,5,8-tetraazaphenanthrene (TAP) as ancillary ligands have been synthesised and characterised. Their attachment onto the surface of gold nanoparticles (AuNPs, average diameter of ca. 2.5 nm) resulted in the formation of two new water-soluble Ru(ii)-AuNP conjugates that combine the advantageous properties of both moieties. Both free complexes show the attractive photophysical properties of Ru(ii) polypyridyl complexes and a rapid cellular uptake in HeLa cervical cancer cells. However, their corresponding gold conjugates displayed lower quantum yields than those determined for the free complexes presumed to be due to an energy transfer quenching of the Ru(ii) luminescence by interaction with the gold surface. Despite their diminished luminescence, confocal fluorescence microscopy studies revealed that the Ru(ii)-AuNP conjugates are successfully internalised into HeLa cells and better tolerated than their free complex counterparts after 24 h incubation, which makes them potential luminescent nanomaterials for bioimaging applications.

Investigating the reactivity of neutral water-soluble Ru(ii)-PTA carbonyls towards the model imine ligands pyridine and 2,2'-bipyridine.

As a continuation of our strategy for preparing new Ru(ii) precursors to be exploited as building blocks in the construction of metal-mediated supramolecular assemblies with improved solubility in water, here we describe the reactivity of selected neutral Ru(ii)–PTA carbonyls (PTA = 1,3,5-triaza-7-phosphaadamantane) towards the model imine ligands pyridine (py) and 2,2′-bipyridine (bpy) and the preparation and characterization of several neutral and cationic water-soluble derivatives: trans,trans,trans-[RuCl2(CO)(py)(PTA)2] (7), cis,cis,trans-[RuCl2(CO)2(py)(PTA)] (9), cis,trans-[Ru(bpy)Cl(CO)(PTA)2]Cl (10), mer-[Ru(bpy)(CO)(PTA)3](Cl)2 (12), cis,trans-[Ru(bpy)(CO)2Cl(PTA)]Cl (13), cis,trans-[Ru(bpy)(CO)2(PTA)2](NO3)2 (14NO3). In addition, we found that light-induced isomerization in some bpy compounds could be induced. The following species, either side-products isolated in low yield or compounds obtained exclusively in solution, were also unambiguously identified: cis,cis,trans-[RuCl2(CO)(py)(PTA)2] (8), trans-[RuCl2(bpy)(CO)(PTA)] (11), cis,cis-[Ru(bpy)Cl(CO)(PTA)2]Cl (15) and cis,cis-[Ru(bpy)(CO)2Cl(PTA)]Cl (16). The X-ray structures of 7, 11·H2O, and 12·7H2O are also reported. All compounds are new and – with few exceptions – show a good solubility in water.

Near-IR/Visible-Emitting Thiophenyl-Based Ru(II) Complexes: Efficient Photodynamic Therapy, Cellular Uptake, and DNA Binding.

Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)2(dtdpq)](ClO4)2 (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)3](ClO4)2 (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH2Cl2 to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 106 M-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above.

Soluble Cytotoxic Ruthenium(II) Complexes with 2-Hydrazinopyridine

New water soluble Ru(II) binary complex [Ru(C5H7N3)(X)(H2O)2] with 2-hydrazinopyridine and its ternary complexes with X = dichloride, oxalate, malonate or pyrophosphate ligands have been synthesized. The complexes have been characterized using elemental analyses, mass, IR, and UV-Vis. spectroscopies, cyclic voltammetry, magnetic susceptibility, and thermal analysis. The complexes are diamagnetic and the electronic spectral data showed that peaks are due to low spin octahedral Ru(II) complexes. The optimized structures of the complexes 1–4 indicate distorted octahedral geometry with bond angles around the ruthenium atom ranged from 80.44° to 99.64°. The values of the electronic energies (−635 to −1145 a.u.), the highest occupied molecular orbital energies (−0.181 to 0.073 a.u.) and lowest unoccupied molecular orbital energies (−0.056 to 0.167 a.u.) indicate the stability of the complexes. The complexes are polarized as indicated from the dipole moment values (9.39–14.27 Debye). The complexes have noticeable cytotoxicity with IC50 (µM): 0.011–0.062 (HepG-2), 0.015–0.080 (MCF-7), 0.015–0.116 (HCT-116), and PC-3 (0.034–0.125).

Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds.

A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an ammonium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.

Water soluble Ru (II)–p‐cymene complexes of chiral aroylthiourea ligands derived from unprotected D/L‐alanine as proficient catalysts for asymmetric transfer hydrogenation of ketones

The newfangled chiral aroylthiourea ligands (L1‐L6) were produced from unprotected D/L‐alanine and their water soluble Ru (II) organometallic catalysts (1–6) were designed from their reaction with [RuCl2(η6‐p‐cymene)]2. The analytical and spectral methods were used to confirm the structure of the ligands and complexes. The solid state structure of L1, 5 and 6 was confirmed by single crystal XRD. The organometallic compounds (1–6) catalyzed the asymmetric transfer hydrogenation of aromatic, heteroaromatic and bulky ketones to yield respective enantiopure secondary alcohols with admirable conversions (up to 99%) and attractive enantiomeric excesses (ee up to 98%), in presence of formic acid and triethylamine in water medium under non‐inert atmospheric conditions.

Water-soluble Ru(II)-anethole compounds with promising cytotoxicity toward the human gastric cancer cell line AGS

AimsRuthenium-based compounds exhibit critical biochemical properties making them suitable for diverse pharmacological applications. The aim of this work was to study the anticancer effects of three ruthenium complexes on a human gastric cancer cell line. Main methodsWe synthetized three [Ru(η6-anethole)(en)X]PF6 complexes, where (en) is ethylenediamine and X is Cl (1), Br (2) or I (3), which were then evaluated by MTT assay, RT-qPCR and flow cytometry on the human gastric cancer cell line AGS. Key findingsCompound 3 exhibited the highest cytotoxicity (IC50 = 11.27 ± 1.08 μM) of the series, with an activity almost three-fold more potent than the commercial drug cisplatin, and also revealed a 4.5-fold less potent cytotoxicity in the human normal gastric cell line GES-1. The exchange of the halogen (Cl, Br or I) on the organometallic compound slightly alters its solubility in PBS and lipophilicity (expressed as Log P). Studies of gene expression revealed that compound 3 induces a significant overexpression of the pro-apoptotic genes Caspase-3, PUMA and DIABLO in the gastric cancer cell line AGS after 6 h. In contrast, only PUMA was significantly overexpressed in the normal gastric cell line GES-1. Compound 3 induced the activation of multiple caspases in AGS cells: a sign of apoptosis. Characterization via single-crystal X-ray diffraction for compound 3 confirmed the key structural features for this type of organometallic complexes. SignificanceOur data suggests that compound 3 may be an interesting anticancer molecule for the treatment of gastric cancer.

Soluble ruthenium(II) with 3,4-diaminobenzoic acid complexes

New four water-soluble Ru(II) with 3,4-diaminobenzoic acid complexes were synthesized. The complexes have been characterized using different tools such as: elemental analysis, mass, infrared, UV–Vis spectroscopy, magnetic susceptibility, thermal analysis and theoretical calculations. The complexes are diamagnetic and the electronic spectral data showed the peaks due to low-spin octahedral Ru(II) complexes. The thermal studies of complexes were investigated by the thermogravimetric analysis. The derivative thermogravimetric analysis has been also used to describe the steps ranges for better precision. The data showed that all complexes have been decomposed in three steps, and the decomposition data are consistent with the proposed formulae of the complexes. The thermal stability of the complexes (1–4) is confirmed by their relatively high overall activation energy ranged (96–207 kJ mol−1). The optimized structures of complexes (1–4) indicate that the complexes have distorted octahedral geometries with bond angles around the ruthenium atom ranged 78.37°–99.08°. The negative values of the electronic energies (− 807 to − 1319 a.u.), the highest occupied molecular orbital energies (− 0.176 to − 0.215 a.u.) and the lowest unoccupied molecular orbital energies (− 0.094 to − 0.138 a.u.) of the complexes indicate the stability of the complexes. The complexes are polarized as indicated from dipole moment values (5.18–13.33 Debye). All complexes are water soluble, neutral, stable and non-hygroscopic. The complexes have noticeable cytotoxicity with IC50 (µM): 0.017–0.083 (MCF-7), 0.014–0.123 (HCT-116), 0.024–0.126 (PC-3) and 0.013–0.056 (HepG-2). New soluble Ru(II) complexes with 3,4-diaminobenzoic acid (DABA) ligand and different secondary ligands have been synthesized and characterized. The complexes are diamagnetic with distorted low-spin octahedral geometries. The thermal decomposition of complexes was studied and the thermodynamic parameters were evaluated. The IC50 values are in the range (0.013–0.089) μΜ.

Theoretical study on photophysical properties of three high water solubility polypyridyl complexes for two-photon photodynamic therapy.

Two-photon photodynamic therapy (TP-PDT) is a very promising treatment that has drawn much attention in recent years due to its ability to penetrate deeper into tissues and minimize the damage to normal cells. Here, the properties of three highly water soluble Ru(ii) and Zn(ii) polypyridyl complexes as photosensitizers (PSs) were examined, including the one-photon and two-photon absorption (OPA and TPA) spectra, singlet-triplet energy gap (ΔH-L), TPA cross-section and spin-orbit coupling constant via Density Function Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT). Their potential therapeutic use as photosensitizers in TP-PDT is proposed, where the reasoning is as follows: first, they possess strong absorption in the therapeutic window; second, the vertical excitation energy is greater than 0.98 eV, which can generate a singlet oxygen species and the remarkable coupling between the S1 and T1 states. Moreover, the spin-orbit matrix elements are greater than 0.24 cm-1 for Ru-bpy and Zn-tpy, indicating that the intersystem spin crossing processes are efficient. It is expected that these complexes will be applied to PSs in TP-PDT, and we hope this research can serve as a guideline for the development of efficient two-photon PSs.

Ring-closing metathesis of unprotected peptides in water.

Ring-closing metathesis (RCM) is an attractive reaction for the preparation of artificially designed peptides. Until now, RCM has been used for fully or partially protected peptides. Herein, the first RCM of unprotected peptides in water was achieved using a water-soluble Ru catalyst.

Transfer hydrogenation of carbon dioxide and bicarbonate from glycerol under aqueous conditions.

The transfer hydrogenation of CO2 from glycerol to afford formic and lactic acid is a highly attractive path to valorizing two waste streams and is a significantly more thermodynamically favorable process than direct CO2 hydrogenation. We report the first homogeneous catalyst for this transformation consisting of a water-soluble Ru N-heterocyclic carbene complex. The catalyst affords lactic and formic acid selectively in the presence of a base at temperatures between 150 and 225 °C. Carbonate salts can also be utilized in place of CO2, affording the same products at higher rates.

NH insertion reactions catalyzed by reusable water-soluble ruthenium(II)-hm-phenyloxazoline complex

A water-soluble Ru(II)-hm-pheox complex was efficiently catalyzed NH insertion of EDA with a broad class of amine derivatives in water/ether biphasic medium to deliver the biologically active precursors α-aminoester products with excellent yields (up to >99%). The products were separated by decantation and the catalyst was washed and reused several times (at least 8 times) without any specific loss of its catalytic activity. The plausible mechanism of the reaction was explained. Additionally, In case of ethylene diamine, the NH insertion product could be transformed to biological active piperazinone compound in high yield. The asymmetric version of this catalytic reaction is under investigation.

Promoter effect of bicarbonate in hydrogenation of cinnamaldehyde catalyzed by a water-soluble Ru(II)-phosphine complex

Abstract The highly selective formation of cinnamalcohol in hydrogenation of trans-cinnamaldehyde with [{RuCl2(mtppms)2}2] + mtppms as catalyst (mtppms = monosulfonated triphenylphosphine) in aqueous solution was substantially accelerated by NaHCO3 (in 20–50 mol% quantities relative to cinnamaldehyde). More than double conversion compared to bicarbonate-free systems was observed at n(NaHCO3)/n(Ru) = 20. Prehydrogenation of the reaction mixture before the addition of cinnamaldehyde resulted in further rate increase (45.3% conversion vs. 13.1% in water). 1H , 13C and 31P NMR studies revealed that formate produced in hydrogenation of bicarbonate facilitated formation of trans-[Ru(H)2(H2O)(mtppms)3], a better catalyst than cis-fac-[Ru(H)2(H2O)(mtppms)3] which is the product of the reaction of [{RuCl2(mtppms)2}2] + mtppms with H2 in the absence of formate (or bicarbonate). Accordingly, NaHCO2 produced even higher rate increase than the same amount of NaHCO3.

Water-Soluble Ruthenium (II) Chiral Heteroleptic Complexes with Amoebicidal in Vitro and in Vivo Activity.

Three water-soluble Ru(II) chiral heteroleptic coordination compounds [Ru(en)(pdto)]Cl2 (1), [Ru(gly)(pdto)]Cl (2), and [Ru(acac)(pdto)]Cl (3), where pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, have been synthezised and fully characterized. The crystal structures of compounds 1-3 are described. The IC50 values for compounds 1-3 are within nanomolar range (14, 12, and 6 nM, respectively). The cytotoxicity for human peripheral blood lymphocytes is extremely low (>100 μM). Selectivity indexes for Ru(II) compounds are in the range 700-1300. Trophozoites exposed to Ru(II) compounds die through an apoptotic pathway triggered by ROS production. The orally administration to infected mice induces a total elimination of the parasite charge in mice faeces 1-2-fold faster than metronidazole. Besides, all compounds inhibit the trophozoite proliferation in amoebic liver abscess induced in hamster. All our results lead us to propose these compounds as promising candidates as antiparasitic agents.

Water soluble Ru(ii)–arene complexes of the antidiabetic drug metformin: DNA and protein binding, molecular docking, cytotoxicity and apoptosis-inducing activity

The incorporation of antidiabetic drug metformin with organometallic Ru(arene) pharmacophore is a promising approach to develop new anticancer agents.