Half-sandwich Iridium Complexes Research Articles

Half-Sandwich Iridium Complexes: A Recyclable and Stable Catalyst for Dehydrogenation of Alcohols to Carboxylic Acids.

A series of acylhydrazone-based N,N-chelate half-sandwich iridium complexes have been synthesized through a facile route in good yields. The dehydrogenation of a series of aromatic and aliphatic primary alcohols to corresponding carboxylic acids has been accomplished catalyzed by the prepared air stable iridium complexes under mild reaction conditions. Carboxylic acids were obtained in high yields under open flask condition with broad substrates and good tolerance to sensitive functional groups. Such a half-sandwich iridium catalyst system exhibited high catalytic activity and stability, and a high TOF of 316.7 h-1 could be achieved with a catalyst loading as low as 0.05 mol %. Furthermore, the sustainable catalyst could be reused at least five times without obviously losing its activity, highlighting its potential application in industry. Molecular structure of iridium complex 1 was confirmed by single-crystal X-ray analysis.

Ferrocene-modified half-sandwich iridium(III) and ruthenium(II) propionylhydrazone complexes and anticancer application

Ferrocene, ruthenium(II) and iridium(III) organometallic complexes, potential substitutes for platinum-based drugs, have shown good application prospects in the field of cancer therapy. Therefore, in this paper, six ferrocene-modified half-sandwich ruthenium(II) and iridium(III) propionylhydrazone complexes were prepared, and the anticancer potential was evaluated and compared with cisplatin. These complexes showed potential in-vitro anti-proliferative activity against A549 cancer cells, especially for Ir-based complexes, and showing favorable synergistic anticancer effect. Meanwhile, these complexes showed little cytotoxicity and effective anti-migration activity. Ir3, the most active complex (ferrocene-appended iridium(III) complex), could accumulate in the intracellular mitochondria, disturb the cell cycle (S-phase), induce the accumulation of reactive oxygen species, and eventually cause the apoptosis of A549 cells. Then, the design of these complexes provides a good structural basis for the multi-active non‑platinum organometallic anticancer complexes.

Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity.

Kinesin spindle protein (KSP) inhibitors are one of the most promising anticancer agents developed in recent years. Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium. Conjugation of 7-chloroquinazolin-4(3H)-one with the pyridine-2-ylmethylimine group and the organometallic moiety resulted in up to a 36-fold increased cytotoxicity with IC50 values in the micromolar and nanomolar range also toward drug-resistant cells. All studied conjugates increased the percentage of cells in the G2/M phase, simultaneously decreasing the number of cells in the G1/G0 phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action.

Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses.

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery.

A single site catalyst supported in mesoporous UiO-66 for catalytic conversion of carbon dioxide to formate

The half-sandwich (tetrazolylpyridyl)iridium(iii) complex shows improved catalytic activity towards hydrogenation of carbon dioxide to formate when supported in a mesoporous m-UiO-66 MOF.

Potent Half-Sandwich 16-/18-Electron Iridium(III) and Ruthenium(II) Anticancer Complexes with Readily Available Amine-Imine Ligands.

The synthesis and biological evaluation of stable 16-electron half-sandwich complexes have remained scarce. We herein present the different coordination modes (16-electron or 18-electron) between half-sandwich iridium(III) complexes and ruthenium(II) complexes derived from the same amine-imine ligands chelating hybrid sp3-N/sp2-N donors. The 16-electron iridium(III) and 18-electron ruthenium(II) complexes with different counteranions were obtained and identified by various techniques. The promising cytotoxicity of these complexes against A549 lung cancer cells, cisplatin-resistant A549/DPP cells, cervical carcinoma HeLa cells, and human hepatocellular liver carcinoma HepG2 cells was observed with IC50 values ranging from 5.4 to 16.3 μM. Moreover, these complexes showed a certain selectivity (selectivity index: 2.1-3.7) toward A549 cells and BEAS-2B normal cells. The variation of metal center, counteranion, 16/18-electron coordination mode, and ligand substituents showed little influence on the cytotoxicity and selectivity of these complexes. The mechanism of action study showed that these complexes could target mitochondria, induce the depolarization of the mitochondrial membrane, and promote the generation of intracellular reactive oxygen species (ROS). Further, the induction of cell apoptosis and the perturbation of the cell cycle in the G0/G1 phase were also observed for these complexes. Overall, it seems that the redox mechanism dominated the anticancer efficacy of these complexes.

Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes Chelating Hybrid sp2-N/sp3-N Donor Ligands to Achieve Improved Anticancer Selectivity.

The biological efficacy of half-sandwich platinum group organometallic complexes of the formula [(η5-Cpx)/(η6-arene)M(XY)Cl]0/+ (XY = bidentate ligands; Cpx = functionalized cyclopentadienyl; M = Ir, Rh, Ru, Os) has received considerable attention due to the significance of the metal center, chelating ligand, and Cpx/arene moieties in defining their anticancer potency and selectivity. With a facile access to the BIAN-derived imine-amine ligands using alkylaluminum as the reductant, we herein described the preparation and characterization of 16 half-sandwich Ir(III), Rh(III), and Ru(II) complexes chelating the hybrid sp2-N/sp3-N donor ligand. A nonplanar five-member metallacycle was confirmed by X-ray single-crystal structures of Ir1-Ir3, Ir7, Rh1, Ru1, and Ru4. The attempt to prepare imine-amido complexes using a base as the deprotonating agent led to the mixture of imine-amine complexes, within which the leaving group Cl- was displaced, and 16-electron imine-amido complexes without Cl-. The half-sandwich imine-amine complexes in this system underwent rapid hydrolysis in aqueous solution, exhibited weak photoluminescence, and showed the ability of binding to CT-DNA and BSA. The cytotoxicity of all imine-amine complexes against A549 lung cancer cell lines, HeLa cervical cancer cell lines, and 4T1 mouse breast cancer cells was determined by an MTT assay. The IC50 values of these complexes were in a range of 5.71-67.28 μM. Notably, most of these complexes displayed improved selectivity toward A549 cancer cells versus noncancerous BEAS-2B cells in comparison with the corresponding α-diimine complexes chelating the sp2-N/sp2-N donor ligand, which have been shown no selectivity in our previous report. The anticancer selectivity of these complexes appeared to be related to the redox-based mechanism including the catalytic oxidation of NADH to NAD+, reactive oxygen species (ROS) generation, and depolarization of the mitochondrial membrane. Further, inducing apoptosis of these complexes in A549 cancer cells and BEAS-2B normal cells also correlated with their anticancer selectivity, indicating the apoptosis mode of cell death in this system. In addition, these complexes could enter A549 cells via energy-dependent pathway and were able to impede the in vitro migration of A549 cells.

Antimicrobial study of ruthenium and iridium half-sandwich complexes containing fluorenyl hydrazonothiazole derivative ligands

A series of six new hydrazineyl-thiazolyl mononuclear complexes (1–6) of the type [(arene)M(κ2 (N∩N)-L)Cl] (M = Ru, Ir, arene: p-cymene or Cp* (pentamethyl cyclopentadienyl); L = bidentate substituted thiazolyl derivatives) have been synthesized and characterized. The complexes have been isolated as neutral mononuclear N∩N chelating metal complexes. Complexes 1–6 were characterized by IR, UV–Vis, NMR, and ESI-MS spectral methods. The solid-state molecular structures of 3 and 4 were determined using single-crystal X-ray diffraction and the geometry of the complexes are pseudo-octahedral, similar to piano stool structures. The N∩N binding mode is through the azomethine nitrogen and the nitrogen of the thiazole ring, forming a five-membered chelating ring. The synthesized ligands and complexes were then tested for their antibacterial properties against three strains of bacterial microorganisms, Staphylococcus aureus (+ve), Klebsiella pneumoniae (−ve), and Escherichia coli (−ve).

Synthesis of half-sandwich ruthenium(II) and iridium(III) complexes containing imidazole-based phosphinite ligands and their use in catalytic transfer hydrogenation of acetophenone with isopropanol

Two ionic liquids (3-(3‑chloro-2-hydroxypropyl)-1-vinyl-1H-imidazol-3-ium chloride and 3-(3‑chloro-2-hydroxypropyl)-1‑butyl‑1H-imidazol-3-ium chloride) were prepared from commercially available, inexpensive 1-vinyl imidazole or 1‑butyl imidazole, respectively, in ethanol at room temperature. Then, these ionic liquids were treated with PPh2Cl to obtain ionic liquid-based phosphinite ligands and the reaction of these phosphinites with [Ru(η6-benzene)(μ-Cl)Cl]2, [Ru(η6−p-cymene)(μ-Cl)Cl]2, or [Ir(η5-C5Me5)(μ-Cl)Cl]2 gave the corresponding ruthenium and iridium complexes. Structures of the synthesized compounds were clarified by multinuclear NMR and IR spectroscopy as well as microanalysis. Furthermore, the complexes were applied as catalysts in the transfer hydrogenation of acetophenone derivatives to afford the corresponding alcohols with high conversions. Notably, [Ru(Ph2POC8H11N2Cl2)(η6-benzene)Cl2] acts as a good catalyst, giving the corresponding alcohols in 97–98% yields in 15 min at 82 °C (TOF ≤ 400 h−1) for the transfer hydrogenation reaction in comparison to analogous complexes. The catalysts are also useful for a variety of related ketone substrates with various electronic and steric regulating groups.

Half-sandwich iridium(III) and rhodium(III) complexes: synthesis, characterization and antifouling properties

The reaction of [(η5-C5Me5)MCl2]2 [M = Ir (1) or Rh (2)] with thiazole ligands (L) at room temperature [L = atz; 2-acetamidothiazole (3) or catz; 5-chloro-2-acetamidothiazole (4)] afforded iridium(III) and rhodium(III) complexes of the type [(η5-C5Me5)M(L)Cl2] [M = Ir; L = atz (5), ctz (6); M = Rh, L = atz (7), catz (8)]. Compounds were characterized by FTIR, NMR (1H and 13C) and mass spectroscopic data. The molecular structures of 5 and 6 have been determined by single-crystal X-ray diffraction. All the compounds were obtained as neutral complexes and the ligand is coordinated monodentate to the metal. The in vitro antibacterial activity of the compounds against ten marine fouling bacteria showed moderate to good activity against the tested marine fouling bacteria.

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent half-sandwich iridium(III) pyridine complexes {[(η5-Cpx)Ir(L)Cl2]} (Ir1-Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G2/M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin.

Half-sandwich iridium complexes with hydrazone ligands: preparation, structure, and catalytic synthesis of cyanosilylethers under air.

A series of hydrazone-based N,O-chelate half-sandwich iridium complexes were synthesized through a facile route with good yields. These air- and moisture-stable iridium complexes exhibited excellent catalytic activity in the cyanosilylether synthesis under mild reaction conditions. Under the catalysis of iridium, various cyanosilylethers with different substituents were obtained through a one-pot reaction of trimethylsilyl cyanide (TMSCN) with carbonyl substrates, with good to excellent yields. The excellent catalytic efficiency, wide substrate range, and mild reaction conditions made this type of iridium catalyst have the potential for industrial applications. All the half-sandwich iridium complexes were well characterized by IR, NMR, and EA analyses. The molecular structure of iridium complex 1 was confirmed by single-crystal X-ray analysis.

Cationic N,S-chelate half-sandwich iridium complexes: synthesis, characterization, anticancer and antiplasmodial activity.

A series of pyrazole-based ligands and their corresponding cationic N,S-chelate half-sandwich iridium complexes were successfully synthesized. All iridium complexes exhibited good anticancer activity against the MCF-7 and MDA-MB-231 human breast cancer cells. The cytotoxic activity of unsubstituted iridium complex 1 is greater than that of cisplatin against MCF-7 cells. In addition, the cationic half-sandwich iridium complexes are also efficient in antiplasmodial study and complex 1 displayed the best activity as its IC50 was observed to be approximately 0.11 μM against the CQS-NF54 strain. These iridium complexes generally exhibited enhanced activity against the CQS-NF54 strain in comparison with that against the CQR-K1 strain. An "IC50 speed assay" investigation against the CQS-NF54 strain indicated complexes 1-3 to be fast-acting complexes that reach their lowest IC50 values within 16 hours. All complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis, and the structure of the iridium complex was confirmed by single-crystal X-ray diffraction.

Increasing Anticancer Activity with Phosphine Ligation in Zwitterionic Half-Sandwich Iridium(III), Rhodium(III), and Ruthenium(II) Complexes.

The synthesis and biological assessment of neutral or cationic platinum group metal-based anticancer complexes have been extremely studied, whereas there are few reports on the corresponding zwitterionic complexes. Herein, the synthesis, characterization, and bioactivity of zwitterionic half-sandwich phosphine-imine iridium(III), rhodium(III), and ruthenium(II) complexes were presented. The sulfonated phosphine-imine ligand and a group of zwitterionic half-sandwich P,N-chelating organometallic complexes were fully characterized by nuclear magnetic resonance (NMR), mass spectrum (electrospray ionization, ESI), elemental analysis, and X-ray crystallography. The solution stability of these complexes and their spectral properties were also determined. Notably, almost all of these complexes showed enhanced anticancer activity against model HeLa and A549 cancer cells than the corresponding zwitterionic pyridyl-imine N,N-chelating iridium(III) and ruthenium(II) complexes, which have exhibited inactive or low active in our previous work. The increase in the lipophilic property and intracellular uptake levels of these zwitterionic P,N-chelating complexes appeared to be associated with their superior cytotoxicity. In addition, these complexes showed biomolecular interactions with bovine serum albumin (BSA). The flow cytometry studies indicated that the representative complex Ir1 could induce early-stage apoptosis in A549 cells. Further, confocal microscopy imaging analysis displayed that Ir1 entered A549 cells through the energy-dependent pathway, targeted lysosome, and could cause lysosomal damage. In particular, these complexes could impede cell migration in A549 cells.

Mitochondrial targeting half-sandwich iridium(III) and ruthenium(II) dppf complexes and in vitro anticancer assay

Considering the potential application of half-sandwich and ferrocenyl-containing organometallic complexes in the area of anticancer, four half-sandwich iridium(III) (IrIII) and ruthenium(II) (RuII) diphenylphosphino ferrocene (dppf) complexes were prepared in this study. Complexes showed favorable anti-proliferation activity towards A549 cell lines compared to cisplatin, meanwhile, which could effectively inhibit cell migration. These complexes followed an energy dependence uptake mechanism, effectively accumulated in mitochondria with a Pearson's Colocalization Coefficient (PCC) of 0.77, decreased the mitochondrial membrane potential, induced a surge of reactive oxygen species, disturbed cell cycle, and eventually led to apoptosis. Western blot assay further confirmed that these complexes induced apoptosis following a mitochondrial pathway. Above all, half-sandwich IrIII and RuII dppf complexes show the prospect of becoming a new multifunctional therapeutic platform for mitochondrial targeted imaging and anticancer drugs.

Iridium(III) and Rhodium(III) Half-Sandwich Coordination Compounds with 11H-Indeno[1,2-b]quinoxalin-11-one Oxime: A Case of Spontaneous Resolution of Rh(III) Complex

Two half-sandwich iridium(III) and rhodium(III) complexes with 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) ligand were prepared by the reaction of the proligand with [M(Cp*)Cl2]2 (M = Ir, Rh) dimers. The reaction between IQ-1 and [Ir(Cp*)Cl2]2 in methanol gave the complex [Ir(Cp*)(IQ-1)Cl] (1), which crystallized in a centrosymmetric space group as a true racemate. Whereas complex [Rh(Cp*)(IQ-1)Cl] (2) in the form of a racemic conglomerate was obtained by the reaction of [Rh(Cp*)Cl2]2 and IQ-1 in methanol. The crystal structures of complexes 1 and 2 (R and S enantiomers) were determined by X-ray diffraction analysis, and the structural features were compared in order to understand the structural factors leading to the spontaneous enantiomer resolution of the rhodium(III) complex. In the crystal packing of 1, intermolecular C–H···C contacts between a pair of enantiomers link the molecules into centrosymmetric dimers and lead to the formation of heterochiral crystals of 1. In contrast, the intramolecular contacts CH···Cl and CH···C in complex 2 bind all three ligands around the chiral Rh(III) metal center. In addition, a combination of intermolecular CH···O and CH···C contacts leads to the formation of a homochiral supramolecular structure. These interactions altogether reinforce the spontaneous resolution in complex 2.

Anticancer application of ferrocene appended configuration-regulated half-sandwich iridium(III) pyridine complexes

Ferrocenyl derivatives and half-sandwich iridium(III) complexes have received extensive attention in the field of anticancer. In this paper, series of configuration-controlled ferrocene-modified half-sandwich iridium(III) pyridine complexes were prepared. The combination of half-sandwich iridium(III) complexes and ferrocenyl unit successfully improved the anticancer activity of these complexes, especially for trans-configurational one towards A549 cells, and the best-performing (FeIr5) was almost 3.5 times more potent than that of cisplatin. In addition, these complexes could inhibit the migration of A549 cells. Complexes can accumulate in intracellular lysosomes (PCC: >0.75), induce lysosomal damage, disturb the cell circle, decrease the mitochondrial membrane potential, improve the intracellular reactive oxygen species (ROS) levels, and eventually lead to apoptosis. Meanwhile, complexes could bind to serum protein following a static quenching mechanism and transport through it. Then, ferrocene-modified half-sandwich iridium(III) pyridine complexes hold the promise as potential organometallic anticancer agents for further investigation.

Half-Sandwich Iridium Complexes with Hydrazone Ligands: Synthesis and Catalytic Activity in N-Alkylation of Anilines or Nitroarenes with Alcohols via Hydrogen Autotransfer.

Here, we synthesize a series of hydrazone-based N,O-chelate half-sandwich iridium complexes through a facile route. All air-stable iridium complexes show high catalytic activity in N-alkylation of a broad scope of aniline derivatives and alcohols with liberating water as the sole byproduct. This reaction provides a smooth route to synthesize diverse monoalkylated amines in good to excellent yields at moderate temperature with a low catalyst loading. Moreover, the challenging N-alkylation process using nitroarene substrates as coupling partners is also carried out in this catalytic system. The mechanistic study shows that the present iridium catalysis process proceeds through a hydrogen borrowing mechanism. All iridium(III) complexes 1-4 are characterized by infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and elemental analysis.

Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine-Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers.

Herein, we present the different coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based on pyridine-amine ligands. The pyridyl-amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl-imine products, and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions (nitrogen/adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction of pyridine-amine ligands with [(η5-C5(CH3)5)MCl2]2 (M = Ir or Rh) in the presence of adventitious oxygen afforded the oxidized pyridyl-imine complexes. The possible mechanism for the oxidation of iridium(III) and rhodium(III) amine complexes was confirmed by the detection of the byproduct hydrogen peroxide. Moreover, the formation of pyridyl-amine complexes was favored when nonpolar solvent CH2Cl2 was used instead of CH3OH. The rarely reported complex with [(η5-Cp*)IrCl3] anions can also be obtained without the addition of NH4PF6. The introduction of the sterically bulky i-Bu group on the bridge carbon of the ligand led to the formation of stable 16-electron pyridyl-amido complexes. The pyridyl-amine iridium(III) and rhodium(III) complexes were also synthesized under a N2 atmosphere, and no H2O2 was detected in the whole process. In particular, the aqueous solution stability and in vitro cytotoxicity toward A549 and HeLa human cancer cells of these complexes were also evaluated. No obvious selectivity was observed for cancer cells versus normal cells with these complexes. Notably, the represented complex 5a can promote an increase in the reactive oxygen species level and induce cell death via apoptosis.

Synthesis and study of organometallic PGM complexes containing 2-(2-pyridyl)benzimidazole as antiplasmodial agents

Six half-sandwich complexes of iridium (III), rhodium (III), and ruthenium (II) (C1-C6) bearing the N,N’-chelated ligand 2-(2-pyridyl)benzimidazole (L) were synthesized and characterized, three of which, bearing the iodido ligand are new. The complexes were isolated as yellow or orange solids in moderate to good yields. The complexes were tested for their ability to catalyse the hydrogenation of NAD+ to NADH at pH 7 at 37 °C. The iridium complexes (C1 and C2) were found to perform the best with NADH yields of up to 74% after one hour. All of the complexes and the ligand were screened for their ability to inhibit growth of the drug-sensitive strain of malaria-causing parasite Plasmodium falciparum, NF54. The complexes containing the rhodium (III) metal centre had the highest activity with the IC50 values for the chlorido (C3) and iodido (C4) complexes determined to be 11.4 µM and 9.65 µM respectively. Both complexes performed better than the ligand (IC50 = 55.9 µM). Complexes bearing the iodido ligand were found to be favourable in both the catalysis as well as the antimalarial assays.