Half-sandwich Iridium Complexes Research Articles

Activation of the Ir-N(pyridine) Bond in Half-Sandwich Tethered Iridium(III) Complexes.

We present four new organometallic half-sandwich iridium(III) complexes of formula [Ir(η5:κ1-C5Me4CH2py)(N,N)](PF6)2, bearing a N,N-chelating ligand [ethylenediamine (en), 1; 1,3-diaminopropane (dap), 2; 2,2'-bipyridine (bipy), 3; 1,10-phenanthroline (phen), 4]; and a derivatized cyclopentadienyl ligand, C5Me4CH2C5H4N, which forms an additional five-membered chelate. The latter is hemilabile, and the Ir-N(py) bond can be reversibly cleaved by various stimuli. The four complexes are unreactive toward hydrolysis at pH 7. Interestingly, 1 and 2 react with hydrochloric acid and formate, and speciation between closed and open tether complexes can be followed by 1H NMR spectroscopy. Complex 1 binds to nucleobase guanine (9-ethylguanine, 9-EtG), yet interaction to calf-thymus DNA was not observed. New X-ray structures of closed tether complexes 1-4 and open tether complexes [Ir(η5-C5Me4CH2pyH)(en)Cl](PF6)2 (1·HCl) and [Ir(η5-C5Me4CH2py)(en)H]PF6 (1·hyd) have been determined. Hydride capture is efficient for 1 and 2. The kinetics of Ir-H bond formation and hydride transfer in a model organic molecule have been investigated, revealing a strong dependence on the temperature. Coincubation of complex 1 with nontoxic concentrations of sodium formate decreases the IC50 value in MCF7 breast cancer cells, indicating the possibility of intracellular activation of the Ir-N(py) tether bond to generate cytotoxic activity via iridium-mediated transfer hydrogenation.

Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions

The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of <1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).

Platinum group complexes containing salicylaldehyde based thiosemicarbazone ligands: Their synthesis, characterization, bonding modes, antibacterial and antioxidant studies

Herein we report the synthesis, characterization, bonding modes, antibacterial and antioxidant studies of half-sandwich ruthenium, rhodium and iridium complexes containing salicylaldehyde based thiosemicarbazone derivatives. All complexes have been prepared by reacting [(arene)MCl2]2 (M = Ru, Rh, Ir) with thiosemicarbazone derivatives (L1, L2, and L3) in 1:2 (M:L) molar ratio respectively. Three mononuclear and six binuclear cationic complexes have been obtained with either chloride or PF6 or both (in the case of binuclear complexes) as their counter ion. The binding modes of the thiosemicarbazone derivatives to the metal center for complexes 1–3, 6 and 8 have been confirmed by single-crystal X-ray diffraction studies. Further, their in-vitro antibacterial activity against gram-positive Staphylococcus aureus and gram-negative Escherichia coli, Klebsiella pneumoniae strains have been tested. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of these complexes have also been evaluated. Antioxidant activity of these compounds have also been tested. DNA binding studies for complexes 1 and 4 have been assessed owing to their good fluorescence intensity and are presented in supplementary information.

Synthesis and properties of cyclic tetracarbene-based organometallic assemblies

A tubular tetranuclear silver(I) N-heterocyclic carbene (NHC) metallacage [Ag4(1)2](PF6)4 was synthesized by in situ deprotonation of a cyclic tetraimidazolium ligand with Ag2O. The interaction of obtained octacarbene-based metallacage with aromatic molecules, especially 4,4′-biphenyldicarboxaldehyde in solution was studied by NMR technique. The 4,4′-biphenyldicarboxaldehyde appearing to be located outside of the cavity with multiple C–H⋯O interactions was further confirmed by X-ray crystallography. Additionally, the reaction of the metallacage [Ag4(1)2](PF6)4 with [Cp∗IrCl2]2 afforded a dinuclear half-sandwich iridium complex [Cp∗2Ir2(1)](PF6)4 that contains two CNC-pincer-ligated Cp∗Ir fragments. The complex [Cp∗2Ir2(1)](PF6)4 was characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography.

Air-Stable Half-Sandwich Iridium Complexes as Aerobic Oxidation Catalysts for Imine Synthesis.

Several N,O-coordinate half-sandwich iridium complexes, 1-5, containing constrained bulky β-enaminoketonato ligands were prepared and clearly characterized. Single-crystal X-ray diffraction characterization of these complexes indicates that the iridium center adopts a distorted octahedral geometry. Complexes 1-5 showed good catalytic efficiency in the oxidative homocoupling of primary amines, dehydrogenation of secondary amines, and the oxidative cross-coupling of amines and alcohols, which furnished various types of imines in good yields and high selectivities using O2 as an oxidant under mild conditions. No distinctive substituent effects of the iridium catalysts were observed in these reactions. The diverse catalytic activity, broad substrate scope, mild reaction conditions, and high yields of the products made this catalytic system attractive in industrial processes.

Structurally Strained Half-Sandwich Iridium(III) Complexes As Highly Potent Anticancer Agents.

Six complexes of formula [Ir(η5:κ1-C5Me4CH2py)(C,N)]PF6, where C5Me4CH2py is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η5:κ1-C5Me4CH2pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1-6, are exceptionally more potent (1-2 orders of magnitude). Additionally, 1-6 disrupt mitochondrial membrane potential (ΔΨm) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.

Lysosome-targeted chemotherapeutics: Anticancer mechanism of N-heterocyclic carbene iridium(III) complex

N-heterocyclic carbenes-modified half-sandwich iridium(III) complex [(η5-C5Me4C6H4C6H5)Ir(C^C)Cl]PF6 (C1) (where C^C is a N-heterocyclic carbene ligand) can effectively prevent the proliferation of human cervical cancer cells. Here, this study aims to investigate the in-deep anticancer effects of this complex on non-small cell lung cancer cells and explore the underlying molecular mechanism. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that iridium(III) complex had potent cytotoxicity studies towards non-small cell lung cancer cells (A549), human lung squamous cells (L78), human cervical cancer cells (Hela) and human bronchial epithelial cells (BEAS-2B). Colocalization and cellular uptake studies were analyzed by confocal microscopy. Notably, C1 targeted lysosomes and entered the cancer cells partially through an energy-dependent pathway, inducing the release of cathepsins and other proteins. These proteins regulated lysosomal-mitochondrial dysfunction, thus leading to the release of cytochrome c (cyt c), which amplified apoptotic signals by activating many downstream pathways such as caspase pathways to promote cell apoptosis. The results showed that the inhibitory mechanism of this organometallic iridium(III) complex may involve caspase-associated apoptosis initiated by the lysosomal-mitochondrial pathway.

Insights into the antiproliferative mechanism of (C^N)-chelated half-sandwich iridium complexes.

Transition metal-based anticancer compounds, as an alternative to platinum derivatives, are raising scientific interest as they may present distinct although poorly understood mechanisms of action. We used a structure-activity relationship-based methodology to investigate the chemical and biological features of a series of ten (C^N)-chelated half-sandwich iridiumIII complexes of the general formula [IrCp*(phox)Cl], where (phox) is a 2-phenyloxazoline ligand forming a 5-membered metallacycle. This series of compounds undergoes a fast exchange of their chlorido ligand once solubilised in DMSO. They were cytotoxic to HeLa cells with IC50 values in the micromolar range and induced a rapid activation of caspase-3, an apoptosis marker. In vitro, the oxidative power of all the complexes towards NADH was highlighted but only the complexes bearing substituents on the oxazoline ring were able to produce H2O2 at the micromolar range. However, we demonstrated using a powerful HyPer protein redox sensor-based flow cytometry assay that most complexes rapidly raised intracellular levels of H2O2. Hence, this study shows that oxidative stress can partly explain the cytotoxicity of these complexes on the HeLa cell line and gives a first entry to their mechanism of action.

Quinoline-triazole half-sandwich iridium(III) complexes: synthesis, antiplasmodial activity and preliminary transfer hydrogenation studies.

Iridium(iii) half-sandwich complexes containing 7-chloroquinoline-1,2,3-triazole hybrid ligands were synthesised and their inhibitory activities evaluated against the Plasmodium falciparum malaria parasite. Supporting computational analysis revealed that metal coordination to the quinoline nitrogen occurs first, forming a kinetic product that, upon heating over time, forms a more stable cyclometallated thermodynamic product. Single crystal X-ray diffraction confirmed the proposed molecular structures of both isolated kinetic and thermodynamic products. Complexation with iridium significantly enhances the in vitro activity of selected ligands against the chloroquine-sensitive (NF54) Plasmodium falciparum strain, with selected complexes being over one hundred times more active than their respective ligands. No cross-resistance was observed in the chloroquine-resistant (K1) strain. No cytotoxicity was observed for selected complexes tested against the mammalian Chinese Hamster Ovarian (CHO) cell line. In addition, speed-of-action assays and β-haematin inhibition studies were performed. Through preliminary qualitative and quantitative cell-free experiments, it was found that the two most active neutral, cyclometallated complexes can act as transfer hydrogenation catalysts, by reducing β-nicotinamide adenine dinucleotide (NAD+) to NADH in the presence of a hydrogen source, sodium formate.

The Fluorine Effect in Zwitterionic Half-Sandwich Iridium(III) Anticancer Complexes.

The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η5-CpR ring. The molecular structures for complexes Ir1-Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD+. The effect of the substituents in the η5-CpR ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes.

Potential anticancer agent for selective damage to mitochondria or lysosomes: Naphthalimide-modified fluorescent biomarker half-sandwich iridium (III) and ruthenium (II) complexes

In this work, five naphthalimide-modified half-sandwich iridium and ruthenium complexes ([(η5-Cpx)Ir(NˆN)Cl]PF6, [(η6-p-cym)Ru(NˆN)Cl]PF6) have been presented. The anticancer activities of the complexes against various cancer cell lines were investigated, among them, complexes 2 and 4 showed better anticancer activity than cisplatin, and their anticancer activity is better than complex 5 without fluorophore. In addition, a series of biological tests of complex 2 were performed using flow cytometry, the results indicated that the complex could induce cell death in a variety of ways. By changing of the ligands, the complexes exhibited different photophysical properties, and the mechanism of action of the complexes entering the cell and inducing apoptosis are different. Moreover, complex 2 successfully targeted mitochondria, while complex 4 targeted lysosomes, causing mitochondrial damage and lysosomal damage to induce apoptosis. Excitingly, complex 2 has good antimetastatic ability to cancer cells. Furthermore, complexes 2 and 4 did not have a significant effect on the NADH binding reaction, but they had a moderate binding ability to BSA.

Similarities and differences in d6 low-spin ruthenium, rhodium and iridium half-sandwich complexes: synthesis, structure, cytotoxicity and interaction with biological targets

In this paper, we discussed the similarities and differences in d6 low-spin half-sandwich ruthenium, rhodium and iridium complexes containing 2,2′-biimidazole (H2biim). Three new complexes, {[RuCl(H2biim)(η6-p-cymene)]PF6}2·H2O (1), [(η5-Cp)RhCl(H2biim)]PF6 (2), and [(η5-Cp)IrCl(H2biim)]PF6 (3), were fully characterized by CHN, X-ray diffraction analysis, UV–Vis, FTIR, and 1H, 13C and 15N NMR spectroscopies. The complexes exhibit a typical pseudooctahedral piano-stool geometry, in which the aromatic arene ring (p-cymene or Cp) forms the seat, while the bidentate 2,2′-biimidazole and chloride ion form the three legs of the piano stool. Moreover, the cytotoxic activities of the compounds were examined in the LoVo, HL-60, MV-4-11, MCF-7 human cancer cell lines and BALB/3T3 normal mouse fibroblasts. Notably, the investigated complexes showed no cytotoxic effects towards the normal BALB/3T3 cell line compared to cisplatin, which has an IC50 value of 2.20 µg. Importantly, 1 displayed the highest activity against HL-60 (IC50 4.35 µg). To predict a binding mode, we explored the potential interactions of the metal complexes with CT-DNA and protein using UV absorption and circular dichroism. The obtained data suggest that the complexes could interact with CT-DNA via an outside binding mode. Moreover, binding of the complexes with the GSH via UV–Vis and ESI mass spectra was determined. Comparative studies have shown that the rhodium complex (2) is the most GSH reactive, which is probably responsible for its deactivation towards LoVo and MCF-7 tumour cells. The influence of the metal ion on the biological activity of isostructural Rh(III) and Ir(III) complexes was an important goal of the presented investigation.

Dual Catalytic Cycle of H2 and H2O Oxidations by a Half-Sandwich Iridium Complex: A Theoretical Study.

While hydrogenase and photosystem II enzymes are known to oxidize H2 and H2O, respectively, a recently reported iridium aqua complex [IrIII(η5-C5Me5){bpy(COOH)2}(H2O)]2+ is able to oxidize both of the molecules and generate energies as in the fuel and solar cells ( Ogo ChemCatChem 2017 , 9 , 4024 - 4028 ). To understand the mechanism behind such an interesting bifunctional catalyst, in the present study, we perform density functional theory (DFT) calculations on the dual catalytic cycle of H2 and H2O oxidations by the iridium aqua complex. In the H2 oxidation, we found that the H-H bond is easily cleaved in a heterolytic fashion, and the resultant iridium hydride complex is significantly stabilized by the presence of H2O molecules, due to dihydrogen bond. The rate-determining step of this reaction is found to be the H2O → H2 ligand substitution with an activation energy of 10.7 kcal/mol. In the H2O oxidation, an iridium oxo complex originating from an oxidation of the iridium aqua complex forms a hydroperoxide complex, where an O-O bond is formed with an activation energy of 21.0 kcal/mol. Such a relatively low activation barrier is possible only when at least two H2O molecules are present in the reaction, allowing the water nucleophilic attack (WNA) mechanism to take place. The present study suggests and discusses in detail six reaction steps required for the dual catalytic cycle to complete.

Synthesis, structural and antimicrobial studies of half-sandwich ruthenium, rhodium and iridium complexes containing nitrogen donor Schiff-base ligands

Synthesis, characterization and antibacterial activity of p-cymene ruthenium, Cp*rhodium and Cp*iridium metal complexes containing pyridyl azine Schiff base ligands have been described. All the complexes have been characterized by various spectroscopic techniques. Molecular structure of complexes 1, 2, 5, 6 and 8 have been obtained by single crystal X-ray diffraction analyses. Spectral studies revealed that ligand L1 bound to metals as neutral mono dentate N donor whereas ligand L2 and L3 revealed the formation of bi dentate NN′ cationic complexes. In vitro antibacterial activity of the complexes was evaluated by the agar well diffusion method using human pathogenic Gram positive bacteria Staphylococcus aureus and Gram-negative bacteria viz., Escherichia coli and Klebsiella pneumonia. Complexes 2–4 does not show any activity against the selected bacteria whereas complexes 1, 5–9 possesses moderate antimicrobial activity and they are more active than the free ligands. The potent activities of the complexes may arise from the coordination, which tends to make metal complexes act as more controlling and potent antimicrobial agents, thus hindering the growth of microorganisms.

Serendipitous Synthesis of Five-Coordinated Half-Sandwich Aminoimine Iridium(III) and Ruthenium(II) Complexes and Their Application as Potent Anticancer Agents.

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-β-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh3) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes.

Lysosome-Targeted Phosphine-Imine Half-Sandwich Iridium(III) Anticancer Complexes: Synthesis, Characterization, and Biological Activity

The synthesis, characterization, and catalytic ability of converting coenzyme NADH to NAD+ and the anticancer activity of half-sandwich iridium(III) complexes with general formula of [(η5-Cpx)Ir(P^N)Cl]PF6 (Cpx: Cp* or biphenyl Cpxbiph derivatives; P^N: various phosphine-imine ligands) were investigated. The crystal structure of the complex Ir4 showed a piano-stool geometry around the iridium(III) center. This type of iridium(III) complexes had sufficient stability in aqueous solution. Most of the complexes showed good anticancer activities toward A549 cancer cells, which were higher than the clinical drug cisplatin. In this series, complex Ir8 displayed the highest anticancer activity against A549 cells (IC50 = 4.7 μM), showing an approximately 4.5-fold more potent activity than cisplatin (IC50 = 21.30 μM). The structure–activity relationship study showed that the cytotoxicity of these complexes may be primarily attributed to the coordination between iridium(III) and the coordinating atoms, and the natur...

Unique Class of Enantiopure N-Heterocyclic Carbene Half-Sandwich Iridium(III) Complexes with Stable Configurations: Probing Five-Membered versus Six-Membered Iridacycles

A unique class of enantiopure N-heterocyclic carbene half-sandwich iridium complexes is reported. These compounds display stable configurations at the metal center, as demonstrated by their chiroptical properties. Remarkably, because of the nature of the naphthalimide molecule, two regioisomers containing five-membered [( R)-2a and ( S)-2a] and six-membered [( R)-2b and ( S)-2b] iridacycles were obtained. Density functional theory calculations are advanced to rationalize their relative stability.

Rhodamine-modified fluorescent half-sandwich iridium and ruthenium complexes: potential application as bioimaging and anticancer agents.

Most half-sandwich metal anticancer complexes are non-fluorescent, which results in an uncertain mechanism of action (MoA). We designed and synthesized eight fluorescent half-sandwich iridium (Ir) and ruthenium (Ru) complexes by introducing rhodamine derivatives into the N^N-chelating ligand. These complexes have features of bio-imaging and anticancer agents and may merit future development as novel anticancer agents.

Mechanistic insights and computational design of half-sandwich iridium and rhodium complexes for hydrogenation of quinoline

DFT calculations reveal a stepwise proton and hydride transfer mechanism for the hydrogenation of quinoline to 1,2,3,4-tetrahydroquinoline catalysed by half-sandwich Cp*Ir(NHC) complexes.

Half-sandwich iridium(III) complexes with α-picolinic acid frameworks and antitumor applications

Eight half-sandwich iridiumIII (IrIII) complexes of the general formula [(η5-Cpxbiph)Ir(O^N)Cl] (Cpxbiph is tetramethyl(biphenyl)cyclopentadienyl, and the O^N is α-picolinic acid chelating ligand and its derivatives) were synthesized and characterized. Compared with cis-platin widely used in clinic, target IrIII complexes showed at most five times more potent antitumor activity against A549 cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. IrIII complexes could be transported by serum albumin, bind with DNA, catalyze the oxidation of nicotinamide-adenine dinucleotid (NADH) and induce the production of reactive oxygen species, which confirmed the antitumor mechanism of oxidation. IrIII complexes could enter A549 cells followed by an energy-dependent cellular uptake mechanism, meanwhile, target the mitochondria and lysosomes with the Pearson's colocalization coefficient of 0.33 and 0.74, respectively, lead to the lysosomal destruction and the change of mitochondrial membrane potential (ΔΨm), and eventually induce apoptosis.