Organoiridium Complex Research Articles

Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent.

While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-IrIII half-sandwich [(η5-CpX)Ir(N∧N)Cl]+-type complexes. In vitro screening identified two lead candidates [(η5-CpXPh)Ir(Ph2Phen)Cl]+ (5, CpXPh = tetramethyl-phenyl-cyclopentadienyl and Ph2Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-CpXBiPh)Ir(Ph2Phen)Cl]+ (6, CpXBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC50 values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported IrIII half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties.

Sulfated Zirconium Metal-Organic Frameworks as Well-Defined Supports for Enhancing Organometallic Catalysis.

Understanding heterogeneous catalysts is a challenging pursuit due to surface site nonuniformity and aperiodicity in traditionally used materials. One example is sulfated metal oxides, which function as highly active catalysts and as supports for organometallic complexes. These applications are due to traits such as acidity, ability to act as a weakly coordinating ligand, and aptitude for promoting transformations via radical cation intermediates. Research is ongoing about the structural features of sulfated metal oxides that imbue the aforementioned properties, such as sulfate geometry and coordination. To better understand these materials, metal-organic frameworks (MOFs) have been targeted as structurally defined analogues. Composed of inorganic nodes and organic linkers, MOFs possess features such as high porosity and crystallinity, which make them attractive for mechanistic studies of heterogeneous catalysts. In this work, Zr6-based MOF NU-1000 is sulfated and characterized using techniques such as single crystal X-ray diffraction in addition to diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The dynamic nature of the sulfate binding motif is found to transition from monodentate, to bidentate, to tridentate depending on the degree of hydration, as supported by density functional theory (DFT) calculations. Heightened Brønsted acidity compared to the parent MOF was observed upon sulfation and probed through trimethylphosphine oxide physisorption, ammonia sorption, in situ ammonia DRIFTS, and DFT studies. With the support structure benchmarked, an organoiridium complex was chemisorbed onto the sulfated MOF node, and the efficacy of this supported catalyst was demonstrated for stoichiometric and catalytic activation of benzene-d6 and toluene with structure-activity relationships derived.

Iridium-Triggered Allylcarbamate Uncaging in Living Cells.

Designing a metal catalyst that addresses the major issues of solubility, stability, toxicity, cell uptake, and reactivity within complex biological milieu for bioorthogonal controlled transformation reactions is a highly formidable challenge. Herein, we report an organoiridium complex that is nontoxic and capable of the uncaging of allyloxycarbonyl-protected amines under biologically relevant conditions and within living cells. The potential applications of this uncaging chemistry have been demonstrated by the generation of diagnostic and therapeutic agents upon the activation of profluorophore and prodrug in a controlled fashion within HeLa cells, providing a valuable tool for numerous potential biological and therapeutic applications.

X-ray tomography of cryopreserved human prostate cancer cells: mitochondrial targeting by an organoiridium photosensitiser

The organoiridium complex Ir[(C,N)2(O,O)] (1) where C, N = 1-phenylisoquinoline and O,O = 2,2,6,6-tetramethyl-3,5-heptanedionate is a promising photosensitiser for Photo-Dynamic Therapy (PDT). 1 is not toxic to cells in the dark. However, irradiation of the compound with one-photon blue or two-photon red light generates high levels of singlet oxygen (1O2) (in Zhang et al. Angew Chem Int Ed Engl 56 (47):14898-14902 https://doi.org/10.1002/anie.201709082,2017), both within cell monolayers and in tumour models. Moreover, photo-excited 1 oxidises key proteins, causing metabolic alterations in cancer cells with potent antiproliferative activity. Here, the tomograms obtained by cryo-Soft X-ray Tomography (cryo-SXT) of human PC3 prostate cancer cells treated with 1, irradiated with blue light, and cryopreserved to maintain them in their native state, reveal that irradiation causes extensive and specific alterations to mitochondria, but not other cellular components. Such new insights into the effect of 1O2 generation during PDT using iridium photosensitisers on cells contribute to a detailed understanding of their cellular mode of action.Graphic abstract

Single‐Crystalline Organoiridium Complex for Gas‐Triggered Chromogenic Switches and Its Applications on CO Detection and Reversible Scavenging

Summary of main observation and conclusionNonporous molecular single crystals of coordinatively unsaturated 16‐electron metallacycle are found to undergo highly selective – yet reversible – binding of CO over CH4, H2, N2, CO2, various volatile organic compounds and water, through binding of the molecule to its metal centers. Carbon monoxide is taken up by black crystals and subsequently liberated from the corresponding orange CO adduct by reversible metal coordination, the structural evidence obtained from in situ X‐ray diffraction. The single‐crystallinity of the metallacycle is retained even after several cycles. The material, when adsorbed on silica, shows remarkable sensitivity and selectivity for CO, allowing visual CO sensing in the solid state. The metallacycle offer the possibility of serving as readily regenerable scavenger for removing trace CO from gas mixtures with N2.

Organoiridium(III) Complexes as Luminescence Color Switching Probes for Selective Detection of Nerve Agent Simulant in Solution and Vapor Phase.

In this work, cationic organoiridium(III) complex based photoluminescent (PL) probes have been developed to selectively detect the chemical warfare nerve agent mimic, diethyl chlorophosphate(DCP) at nanomolar range by distinct bright green to orange-red luminescence color switching (on-off-on) in solution as well as in the vapor phase. Interference of other chemical warfare agents (CWAs) and their mimics was not observed either by PL spectroscopy or with the naked-eye in solution and gas phase. The detection was attained via a simultaneous nucleophilic attack of two -OH groups of the 4,7-dihydroxy-1,10-phenanthroline ligand with DCP by forming bulkier phosphotriester. The detailed reaction mechanism was established through extensive 1H NMR titration, 31P NMR, and ESI-MS analysis. Finally, a test paper strip and solid poly(ethylene oxide) (PEO) film with iridium(III) complex 1[PF6] were fabricated for the vapor-phase detection of DCP. The solution and vapor-phase detection properties of these luminescent Ir(III) complexes can offer a worthy approach into the design of new metal complex based PL switching probes for chemical warfare agents.

A dry chemical method for dispersing Ir nanoparticles in the pores of activated carbon and their X-ray absorption spectroscopy analysis

Ir nanoparticles are finely dispersed inside the pores of activated carbon (AC) via the gas phase adsorption of an organoiridium complex in the AC and subsequent heat treatment. X-ray absorption spectroscopy reveals the structure of the supported Ir.

A cationic organoiridium(iii) complex-based AIEgen for selective light-up detection of rRNA and nucleolar staining.

A green emissive cationic organoiridium(iii) complex, 2[PF6], with a benzimidazole-substituted 1,2,3-triazole-pyridine (BiPT) ligand has been synthesized for target-specific cellular imaging and selective detection of ribosomal RNA (rRNA) over other competitive biomolecules in aqueous buffer solution at physiological pH. Complex 2 shows aggregation-induced emission enhancement (AIEE) properties and forms nano-aggregates in the presence of poor solvents. DFT and TD-DFT-based quantum mechanical calculations were performed to substantiate some photophysical features and to establish the intermolecular π-π interactions which detain the vibrational as well as rotational motions to form the aggregates, resulting in enhanced photoluminescence (PL). To corroborate the formation of nano-aggregates and to understand the morphology of the aggregated particles, dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) measurements were performed. 2[PF6] showed low cytotoxicity and good biocompatibility and was successfully employed in organelle-specific intracellular imaging. The in vivo and in vitro photoluminescence investigations affirmed that the probe stains cell nucleoli and selectively binds rRNA. It is assumed that the supramolecular π-π interactions between the benzimidazole of the BiPT ligand and the secondary structures of rRNA may facilitate aggregation and enable PL enhancement.

A Single Organoiridium Complex Generating Highly Active Catalysts for both Water Oxidation and NAD+/NADH Transformations

The complex [Cp*Ir(pica)Cl] (1; pica = picolinamidate = κ2-pyridine-2-carboxamide) was found to be an effective catalyst for both water oxidation to molecular oxygen and NAD+/NADH transformations, which are the key reactions of light-dependent natural photosynthesis. In particular, 1 exhibits high activity in water oxidation driven by CAN and NaIO4. With the former, the initial TOF exceeds that of [Cp*Ir(pic)Cl] (2; pic = picolinate = κ2-pyridine-2-carboxylate), which is the fastest iridium catalyst reported to date, whereas with NaIO4 it compares well with the best catalysts. 1 exhibits top performances also in the hydrogenation of NAD+ with HCOOK, leading to the regiospecific formation of 1,4-NADH (pH 7) with TOF = 143 h–1, which is about 3 times higher than the previous highest value (54 h–1) reported for [Cp*Ir(4-(1H-pyrazol-1-yl-κN2)benzoic acid)(H2O)]SO4 (3). The activity seems to be critically affected by the presence of the NH functionality, as indicated by its drop of about 1 order of magnitude w...

Reduction- and pH-Sensitive Hyaluronan Nanoparticles for Delivery of Iridium(III) Anticancer Drugs.

The organoiridium(III) complex (Ir(III)) [(η5-Cpxbiph)Ir(phpy) (py)]PF6 containing π-bonded biphenyltetramethylcyclopentadienyl(Cpxbiph), C∧N-chelated phenylpyridine(phpy), and pyridine (py) ligands has more potent antitumor activity as a new generation of drug than cisplatin toward various cancer cells. However, poor site-specific delivery, low solubility, and poor tumor penetration are common limitations of chemotherapy drugs. To develop CD44-targetable, pH-, and reduction-responsive drug delivery systems for Ir(III) drugs, the amphiphilic hyaluronan (HA)-based conjugates of HA-cystamin-pyrenyl (HA-ss-Py) containing disulfide bonds and HA-pyrenyl (HA-Py) were designed. The Ir(III) drug was readily loaded into these two amphiphilic conjugates and nanoparticles were formed. Dynamic light scattering (DLS) studies showed that the micelles formed from HA-ss-Py were sufficiently stable under physiological conditions, but were prone to rapid dissociation in reducing environments (20 mM glutathione (GSH)). In subsequent confocal microscopy analyses, A549 cancer cells efficiently internalized HA-based micelles. Moreover, in vitro cytotoxicity assays in A549 cells demonstrat that Ir-loaded HA-based nanoparticles have higher cytotoxicity than the free Ir(III) anticancer drug. Finally, systemic administration of Ir(III)-loaded HA-ss-Py nanoparticles enhanced tumor inhibition in vivo, and the corresponding biodistribution experiments showed that HA-ss-Py micelles accumulate in tumors. Overall, our results suggest that HA-ss-Py micelles have a great potential to be used as an effective Ir(III) drug carrier for targeted cancer therapy.

Catalytic Formation of Hydrogen Peroxide from Coenzyme NADH and Dioxygen with a Water-Soluble Iridium Complex and a Ubiquinone Coenzyme Analogue.

A ubiquinone coenzyme analogue (Q0: 2,3-dimethoxy-5-methyl-1,4-benzoquinone) was reduced by coenzyme NADH to yield the corresponding reduced form of Q0 (Q0H2) in the presence of a catalytic amount of a [C,N] cyclometalated organoiridium complex (1: [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))benzoic acid-κC(3))(H2O)]2SO4) in water at ambient temperature as observed in the respiratory chain complex I (Complex I). In the catalytic cycle, the reduction of 1 by NADH produces the corresponding iridium hydride complex that in turn reduces Q0 to produce Q0H2. Q0H2 reduced dioxygen to yield hydrogen peroxide (H2O2) under slightly basic conditions. Catalytic generation of H2O2 was made possible in the reaction of O2 with NADH as the functional expression of NADH oxidase in white blood cells utilizing the redox cycle of Q0 as well as 1 for the first time in a nonenzymatic homogeneous reaction system.

Near-infrared triggered generation of reactive oxygen species from upconverting nanoparticles decorated with an organoiridium complex.

Recently, research efforts have been focused on developing near-infrared perturbable nanoparticles to sensitize photostimulable molecules for the production of reactive oxygen species. Research in this direction is looking to broaden the use of photodynamic therapy, an indispensable clinical tool for cancer therapeutics, which relies on the photoexcitation of a suitable photosensitizer, to convert light into reactive oxygen species that are toxic to cells. To date most commercially available photosensitizers are excited with high energy light (UV or visible) presenting disadvantages that limit the clinical use of this technique to cancers that are on or near the surface of the skin. Here, we develop a hybrid platform capable of near-infrared triggered generation of reactive oxygen species. This hybrid nanostructure is based on LiYF4:Tm3+,Yb3+ nanoparticles, which are capable of producing strong UV emissions, following excitation at 980 nm, through a multiphoton process known as upconversion. When appropriately surface functionalized with an organoiridium complex, excitation at 980 nm produces a strong UV emission, which is absorbed by the organoiridium molecules on the surface, in turn generating reactive oxygen species. Moreover, the effect of the organoiridium concentration on the surface of the upconverting nanoparticles as well as the nature of the sensitization process is discussed.

Catalytic hydrogen production from paraformaldehyde and water using an organoiridium complex

Paraformaldehyde was decomposed using an organoiridium complex (1, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))benzoic acid-κC(3))(H2O)]2SO4) as a catalyst in water to produce H2 and CO2 in a 2 : 1 molar ratio at room temperature. The catalytic cycle is composed of the reduction of 1 by paraformaldehyde under basic conditions to produce formic acid and the hydride complex, which reacts with protons to produce H2. Formic acid further decomposed to H2 and CO2 with 1.

The Potent Oxidant Anticancer Activity of Organoiridium Catalysts

AbstractPlatinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5‐Cpxbiph)Ir(phpy)(Cl)] (1‐Cl), which contains π‐bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C^N‐chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5‐Cpxbiph)Ir(phpy)(py)]+ (1‐py) aquates slowly, and is more potent (in nanomolar amounts) than both 1‐Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1‐py from rapid reaction with intracellular glutathione. The high potency of 1‐py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.

The Potent Oxidant Anticancer Activity of Organoiridium Catalysts

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5-Cpxbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C∧N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5-Cpxbiph)Ir(phpy)(py)]+ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.

Catalytic oxidation of formic acid by dioxygen with an organoiridium complex

Catalytic oxidation of formic acid by dioxygen occurred efficiently using an organoiridium complex as a catalyst in a water-containing organic solvent as well as in water at ambient temperature.

ChemInform Abstract: Organometallic Complexes of the Platinum Metals: Synthesis, Structure, and Catalytic Applications

AbstractReview: 6 refs.

Hydrogen storage and evolution catalysed by metal hydride complexes

The storage and evolution of hydrogen are catalysed by appropriate metal hydride complexes. Hydrogenation of carbon dioxide by hydrogen is catalysed by a [C,N] cyclometalated organoiridium complex, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))benzoic acid-κC(3))(OH(2))](2)SO(4) [Ir-OH(2)](2)SO(4), under atmospheric pressure of H(2) and CO(2) in weakly basic water (pH 7.5) at room temperature. The reverse reaction, i.e., hydrogen evolution from formate, is also catalysed by [Ir-OH(2)](+) in acidic water (pH 2.8) at room temperature. Thus, interconversion between hydrogen and formic acid in water at ambient temperature and pressure has been achieved by using [Ir-OH(2)](+) as an efficient catalyst in both directions depending on pH. The Ir complex [Ir-OH(2)](+) also catalyses regioselective hydrogenation of the oxidised form of β-nicotinamide adenine dinucleotide (NAD(+)) to produce the 1,4-reduced form (NADH) under atmospheric pressure of H(2) at room temperature in weakly basic water. In weakly acidic water, the complex [Ir-OH(2)](+) also catalyses the reverse reaction, i.e., hydrogen evolution from NADH to produce NAD(+) at room temperature. Thus, interconversion between NADH (and H(+)) and NAD(+) (and H(2)) has also been achieved by using [Ir-OH(2)](+) as an efficient catalyst and by changing pH. The iridium hydride complex formed by the reduction of [Ir-OH(2)](+) by H(2) and NADH is responsible for the hydrogen evolution. Photoirradiation (λ > 330 nm) of an aqueous solution of the Ir-hydride complex produced by the reduction of [Ir-OH(2)](+) with alcohols resulted in the quantitative conversion to a unique [C,C] cyclometalated Ir-hydride complex, which can catalyse hydrogen evolution from alcohols in a basic aqueous solution (pH 11.9). The catalytic mechanisms of the hydrogen storage and evolution are discussed by focusing on the reactivity of Ir-hydride complexes.

Organometallic complexes of the platinum metals: Synthesis, structure, and catalytic applications

Reaction of a group of N-(aryl)picolinamides (pic-R) with [Ru(PPh3)2(CO)2Cl2] in refluxing 2-methoxyethanol in the presence of a base affords hydrido complexes of two types (1-R and 2-R), which are geometric isomers. Similar reaction with N-(naphthyl)picolinamide (pic-nap) yields an organoruthenium complex (3) via formation of a hydrido intermediate. Reaction of 2-(arylazo)phenols (ap-R) with [Ir(PPh3)3Cl] in refluxing ethanol affords a mono-hydrido intermediate (4-R), a di-hydrido intermediate (5-R) and an organoiridium complex (6-R) as the final product, where the azo-ligand is coordinated as CNO-donor. Reaction of ap-R ligands with [Rh(PPh3)3Cl] yields organorhodium complexes (7-R) analogous to 6-R, but without any hydrido intermediate. N-(2′-hydroxyphenyl)benzaldimines (hpbz-R) react with [Rh(PPh3)3Cl] to yield a group of organorhodium complexes (8-R), where the hpbz-R ligands are coordinated in CNO-fashion. Upon interaction with [Ir(PPh3)3Cl] 2-(2′,6′-dimethylphenylazo)-4-methylphenol (dmap) undergoes a methyl C–H activation and affords organoiridium complex 9, while 2-(2′-methylphenylazo)-4-methylphenol (mmap) undergoes a phenyl C–H activation and gives organoiridium complex 10. Reaction of benzaldehyde thiosemicarbazones (bztsc-R) with [Pd(PPh3)2Cl2], carried out with the expectation of inducing CNS-mode of coordination, actually has yielded complexes (11-R) where the bztsc-R is coordinated in an uncommon NS-mode forming a five-membered chelate ring associated with a restricted rotation around the imine (C=N) bond. These palladium complexes are found to catalyse C–C cross coupling reactions very efficiently. Crystal structures of selected complexes of each type have been determined by X-ray crystallography. If an alkyl or aryl C–H bond of a judiciously chosen ligand is brought in close proximity to a platinum metal-bound hydride or chloride by coordination through regular donor atoms (as in I), then facile activation of that C–H bond takes place leading to the formation of cyclometallated species (II).

Hydrogen Evolution from Aliphatic Alcohols and 1,4-Selective Hydrogenation of NAD+ Catalyzed by a [C,N] and a [C,C] Cyclometalated Organoiridium Complex at Room Temperature in Water

A [C,N] cyclometalated Ir complex, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))benzoic acid-κC(3))(H(2)O)](2)SO(4) [1](2)·SO(4), was reduced by aliphatic alcohols to produce the corresponding hydride complex [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))-benzoate-κC(3))H](-)4 at room temperature in a basic aqueous solution (pH 13.6). Formation of the hydride complex 4 was confirmed by (1)H and (13)C NMR, ESI MS, and UV-vis spectra. The [C,N] cyclometalated Ir-hydride complex 4 reacts with proton to generate a stoichiometric amount of hydrogen when the pH was decreased to pH 0.8 by the addition of diluted sulfuric acid. Photoirradiation (λ > 330 nm) of an aqueous solution of the [C,N] cyclometalated Ir-hydride complex 4 resulted in the quantitative conversion to a unique [C,C] cyclometalated Ir-hydride complex 5 with no byproduct. The complex 5 catalyzed hydrogen evolution from ethanol in a basic aqueous solution (pH 11.9) under ambient conditions. The 1,4-selective catalytic hydrogenation of β-nicotinamide adenine dinucleotide (NAD(+)) by ethanol was also made possible by the complex 1 to produce 1,4-dihydro-β-nicotinamide adenine dinucleotide (1,4-NADH) at room temperature. The overall catalytic mechanism of hydrogenation of NAD(+), accompanied by the oxidation of ethanol, was revealed on the basis of the kinetic analysis and detection of the reaction intermediates.