Mitochondrial‐DNA‐Targeted IrIII‐Containing Metallohelices with Tunable Photodynamic Therapy Efficacy in Cancer Cells

The development of DNA‐targeted photodynamic therapy (PDT) agents for cancer treatment has drawn substantial attention. Herein, the design and synthesis of dinuclear Ir^III‐containing luminescent metallohelices with tunable PDT efficacy that target mitochondrial DNA in cancer cells are reported. The metallohelices are fabricated using dynamic imine‐coupling chemistry between aldehyde end‐capped fac‐Ir(ppy)₃ handles and linear alkanediamine spacers, followed by reduction of the imine linkages. The length and odd–even character of the diamine alkyl linker determined the stereochemistry (helicates vs. mesocates). Compared to the helicates, the mesocates exhibit improved apoptosis‐induction upon white‐light irradiation. Molecular docking studies indicate that the mesocate with a proper length of diamine spacers shows stronger affinity for the minor groove of DNA. This study highlights the potential of DNA‐targeting Ir^III‐containing metallohelices as PDT agents.     

Gold(III)–pyrrolidinedithiocarbamato Derivatives as Antineoplastic Agents

Transition metals offer many possibilities in developing potent chemotherapeutic agents. They are endowed with a variety of oxidation states, allowing for the selection of their coordination numbers and geometries via the choice of proper ligands, leading to the tuning of their final biological properties. We report here on the synthesis, physico-chemical characterization, and solution behavior of two gold(III) pyrrolidinedithiocarbamates (PDT), namely [Au^IIIBr₂(PDT)] and [Au^IIICl₂(PDT)]. We found that the bromide derivative was more effective than the chloride one in inducing cell death for several cancer cell lines. [Au^IIIBr₂(PDT)] elicited oxidative stress with effects on the permeability transition pore, a mitochondrial channel whose opening leads to cell death. More efficient antineoplastic strategies are required for the widespread burden that is cancer. In line with this, our results indicate that [Au^IIIBr₂(PDT)] is a promising antineoplastic agent that targets cellular components with crucial functions for the survival of tumor cells.     

Synthesis and photophysical properties of Ir<Superscript>III</Superscript>-Ln<Superscript>III</Superscript> (Ln = Nd,Yb, Er) bimetallic complexes containing bipyrimidines as bridging ligands

Bipyrimidines have been chosen as (N∧N)(N∧N) bridging ligands for connecting metal centers. Ir^III-Ln^III (Ln = Nd, Yb, Er) bimetallic complexes [Ir(dfppy)₂(μ-bpm)Ln(TTA)₃]Cl were synthesized by using Ir(dfppy)₂(bpm)Cl as the ligand coordinating to lanthanide complexes Ln(TTA)₃·2H₂O. The stability constants between Ir(dfppy)₂(bpm)Cl and lanthanide ions were measured by fluorescence titration. The obvious quenching of visible emission from Ir^III complex in the Ir^III-Ln^III (Ln = Nd, Yb, Er) bimetallic complexes indicates that energy transfer occurred from Ir^III center to lanthanides. NIR emissions from Nd^III, Yb^III, and Er^III were obtained under the excitation of visible light by selective excitation of the Ir^III-based chromophore. It was proven that Ir(dfppy)₂(bpm)Cl as the ligand could effectively sensitize NIR emission from Nd^III, Yb^III, and Er^III.     

Triphenylamine and carbazole‐modified iridiumIII 2‐phenylpyridine complexes: Synthesis,anticaner application and targeted research

Four half‐sandwich iridium^III (Ir^III) triphenylamine or carbazole‐modified 2‐phenylpyridine (TPA/Cz‐PhPy) complexes ([(η⁵‐Cp*)Ir(C^N)Cl]) were synthesized and characterized. Compared with cisplatin, these complexes show higher activity to A549, HepG2 and HeLa cells, with the IC₅₀ values changed from 2.5 ± 0.1 μM to 14.8 ± 2.6 μM. Additionally, complexes could effectively prevent the migration of cancer cells. Ir^III TPA/Cz‐PhPy complexes could bind to protein and transport through serum protein, catalyze the oxidation of nicotinamide‐adenine dinucleotid (NADH) and induce the accumulation of reactive oxygen species, and eventually lead to apoptosis, which was also confirmed by flow cytometry. Moreover, prominent targeted fluorescence property confirmed that Ir^III TPA/Cz‐PhPy complexes were involved in non‐energy dependent intracellular uptake mechanism, effectively accumulated in lysosomes and damage the integrity of acidic lysosomes, and eventually induce cell death. Above all, TPA/Cz‐appended half‐sandwich Ir^III phenylpyridine complexes are promising anticancer agents with dual functions, including migration inhibition and lysosomal damage.     

meso‐(2‐Pyridyl)‐boron(III)‐subporphyrin: Perimeter Iridium(III) Coordination

Peripherally metalated porphyrinoids are promising functional π‐systems displaying characteristic optical, electronic, and catalytic properties. In this work, 5‐(2‐pyridyl)‐ and 5,10,15‐tri(2‐pyridyl)‐B^III‐subporphyrins were prepared and used to produce cyclometalated subporphyrins by reactions with [Cp*IrCl₂]₂, which proceeded through an efficient C?H activation to give the corresponding mono‐ and tri‐Ir^III complexes, respectively. While the mono‐Ir^III complex was obtained as a diastereomeric mixture, a C₃‐symmetric tri‐Ir^III complex with the three Cp*‐units all at the concave side was predominantly obtained in a high yield of 90 %, which displays weak NIR phosphorescence even at room temperature in degassed CH₂Cl₂, differently from the mono‐Ir^III complexes.     

Encapsulation and Enhanced Luminescence Properties of IrIII Complexes within a Hexameric Self‐Assembled Capsule

Encapsulation and luminescence studies of [Ir(ppy)₂(bpy)]Cl (ppy=2‐phenylpyridinate, bpy=2,2′‐bipyridine) within a hexameric resorcinarene capsule are reported. One Ir^III complex cation was encapsulated within the capsule, as demonstrated by NMR and dynamic light scattering (DLS) studies. The emission color of the Ir^III complex was drastically changed from orange to yellow by encapsulation, in contrast with the lack of significant changes in the absorption spectrum. The hexameric capsule effectively hampers the non‐radiative pathway to increase both the luminescence quantum yield and the exited state lifetime. The luminescent properties of the encapsulated Ir^III complex depend on the ratio of Ir^III complex to the resorcinarene monomer as well as the concentration of resorcinarene monomer owing to the reversible process of self‐assembly of the hexameric capsule. Quenching experiments revealed that the Ir^III complex in the capsule was effectively separated from quenchers.     

Excited state properties of IrIII(phpy)2(naphthylalaninate) with phpyH = 2-phenylpyridine: Energy transfer and luminescence

The complex Ir^III(phpy)₂(nala) with phpyH = 2-phenylpyridine and nalaH = 3-(2-naphthyl)alanine was prepared and characterized. The electronic spectrum of the complex shows long-wavelength absorptions which are attributed to the Ir^III(phpy)₂ chromophore. The lowest-energy excited state is a metal-to-ligand charge transfer (MLCT) triplet which is emissive under ambient conditions. Excitation of the naphthyl chromophore at shorter wavelength is followed by an efficient energy transfer to the Ir^III(phpy)₂ fragment.     

Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated IrIII Complex Conjugated to a Far‐Red Emitting Coumarin

Although cyclometalated Ir^III complexes have emerged as promising photosensitizers for photodynamic therapy, some key drawbacks still hamper clinical translation, such as operability in the phototherapeutic window and reactive oxygen species (ROS) production efficiency and selectivity. In this work, a cyclometalated Ir^III complex conjugated to a far‐red‐emitting coumarin, Ir^III–COUPY, is reported with highly favourable properties for cancer phototherapy. Ir^III–COUPY was efficiently taken up by HeLa cells and showed no dark cytotoxicity and impressive photocytotoxicity indexes after irradiation with green and blue light, even under hypoxia. Importantly, a clear correlation between cell death and intracellular generation of superoxide anion radicals after visible light irradiation was demonstrated. This strategy opens the door to novel fluorescent photodynamic therapy agents with promising applications in theragnosis.     

Tuning the Excited State of Water‐Soluble IrIII‐Based DNA Intercalators that are Isostructural with [RuII(NN)2(dppz)] Light‐Switch Complexes

The synthesis of two new Ir^III complexes which are effectively isostructural with well‐established [Ru(NN)₂(dppz)]²⁺ systems is reported (dppz=dipyridophenazine; NN=2,2′‐bipyridyl, or 1,10‐phenanthroline). One of these Ir^III complexes is tricationic and has a conventional N₆ coordination sphere. The second dicationic complex has a N₅C coordination sphere, incorporating a cyclometalated analogue of the dppz ligand. Both complexes show good water solubility. Experimental and computational studies show that the photoexcited states of the two complexes are very different from each other and also differ from their Ru^II analogues. Both of the complexes bind to duplex DNA with affinities that are two orders of magnitude higher than previously reported Ir(dppz)‐based systems and are comparable with Ru^II(dppz) analogues.     

Tuning the Cellular Uptake Properties of Luminescent Heterobimetallic Iridium(III)–Ruthenium(II) DNA Imaging Probes

The synthesis of two new luminescent dinuclear Ir^III–Ru^II complexes containing tetrapyrido[3,2‐a:2′,3′‐c:3′′,2′′‐h:2′′′,3′′′‐j]phenazine (tpphz) as the bridging ligand is reported. Unlike many other complexes incorporating cyclometalated Ir^III moieties, these complexes display good water solubility, allowing the first cell‐based study on Ir^III–Ru^II bioprobes to be carried out. Photophysical studies indicate that emission from each complex is from a Ru^II excited state and both complexes display significant in vitro DNA‐binding affinities. Cellular studies show that each complex is rapidly internalised by HeLa cells, in which they function as luminescent nuclear DNA‐imaging agents for confocal microscopy. Furthermore, the uptake and nuclear targeting properties of the complex incorporating cyclometalating 2‐(4‐fluorophenyl)pyridine ligands around its Ir^III centre is enhanced in comparison to the non‐fluorinated analogue, indicating that fluorination may provide a route to promote cell uptake of transition‐metal bioprobes.     

Novel Phosphorescent Hydrogels Based on an IrIII Metal Complex

Novel phosphorescent hydrogels have been explored by immobilizing an Ir^III metal complex into the matrices of hydrogels. FTIR spectra demonstrate that the Ir^III–PNaAMPS hydrogel is achieved by irreversible incorporation of positively charged [Ir(ppy)₂(dmbpy)]Cl (ppy = 2‐phenylpyrine, dmbpy = 4,4′‐dimethyl‐2,2′‐bipyridine) into negatively charged poly(2‐acrylamido‐2‐methylpropane sulfonic acid sodium) (PNaAMPS) hydrogel via electrostatic interaction. The photoluminescent spectra indicate that the Ir^III–PNaAMPS hydrogel exhibits stable phosphorescence. In vitro cultivation of human retinal pigment epithelial cells demonstrates the cytocompatibility of the Ir^III–PNaAMPS hydrogel. This work herein represents a facile pathway for fabrication of phosphorescent hydrogels.     

Sensitized near-infrared emission of Yb from an Ir–Yb bimetallic complex

A new cyclometalated ligand 1,3-dimethyl-5-phenyl-1H-[1,2,4]-triazole (pdt) was designed and synthesized. And the corresponding Ir^III complex Ir(pdt)₂(phen5f) (phen5f stands for 4,4,5,5,5-pentafluoro-1-(1′,10′-phenanthrolin-2′-yl)-pentane-1,3-dionate) was obtained. According to the measurement of the lowest triplet state energy level of Ir(pdt)₂(phen5f), it is suitable for sensitizing NIR (near-infrared) lanthanide ions instead of Eu^III. The bimetallic complex [(pdt)₂Ir(μ-phen5f)YbCl₂ · 2CH₃CH₂OH · H₂O]Cl was synthesized by the approach of “complexes as ligands”. Data showed that the emission quenching was observed in the solid state when the Ir^III–Yb^III complex was compared with the Ir^III complex, which implied that energy transfer might occur from Ir^III complex-ligand to Yb^III ion. Upon irradiation of the MLCT (metal-to-ligand charge transfer) absorption of Ir(pdt)₂(phen5f), the characteristic emission of Yb^III was obtained with the peak around 978 nm.     

Protein Labelling with Versatile Phosphorescent Metal Complexes for Live Cell Luminescence Imaging

To take advantage of the luminescent properties of d⁶ transition metal complexes to label proteins, versatile bifunctional ligands were prepared. Ligands that contain a 1,2,3‐triazole heterocycle were synthesised using Cu^I catalysed azide–alkyne cycloaddition “click” chemistry and were used to form phosphorescent Ir^III and Ru^II complexes. Their emission properties were readily tuned, by changing either the metal ion or the co‐ligands. The complexes were tethered to the metalloprotein transferrin using several conjugation strategies. The Ir^III/Ru^II–protein conjugates could be visualised in cancer cells using live cell imaging for extended periods without significant photobleaching. These versatile phosphorescent protein‐labelling agents could be widely applied to other proteins and biomolecules and are useful alternatives to conventional organic fluorophores for several applications.     

Luminescent Bimetallic Lanthanide Bioprobes for Cellular Imaging with Excitation in the Visible‐Light Range

A series of homoditopic ligands H₂L^CX (X=4–6) has been designed to self‐assemble with lanthanide ions (Ln^III), resulting in neutral bimetallic helicates of overall composition [Ln₂(L^CX)₃] with the aim of testing the influence of substituents on the photophysical properties, particularly the excitation wavelength. The complex species are thermodynamically stable in water (log β₂₃ in the range 26–28 at pH 7.4) and display a metal‐ion environment with pseudo‐D₃ symmetry and devoid of coordinated water molecules. The emission of Eu^III, Tb^III, and Yb^III is sensitised to various extents, depending on the properties of the ligand donor levels. The best helicate is [Eu₂(L^C5)₃] with excitation maxima at 350 and 365 nm and a quantum yield of 9 %. The viability of cervix cancer HeLa cells is unaffected when incubated with up to 500 μm of the chelate during 24 h. The helicate permeates into the cells by endocytosis and locates into lysosomes, which co‐localise with the endoplasmatic reticulum, as demonstrated by counterstaining experiments. The relatively long excitation wavelength allows easy recording of bright luminescent images on a confocal microscope (λ_exc=405 nm). The new lanthanide bioprobe remains undissociated in the cell medium, and is amenable to facile derivatisation. Examination of data for seven Eu^III and Tb^III bimetallic helicates point to shortcomings in the phenomenological rules of thumb between the energy gap ΔE(³ππ*–⁵D_J) and the sensitisation efficiency of the ligands.     

Self‐Assembled Triple‐Stranded Lanthanide Dimetallic Helicates with a Ditopic Ligand Derived from Bis(benzimidazole)pyridine and Featuring an (4‐Isothiocyanatophenyl)ethynyl Substituent

Bis(2‐{6‐(diethylcarbamoyl)‐4‐[(4‐isothiocyanatophenyl)ethynyl]pyridin‐2′‐yl}‐1‐ethylbenzimidazol‐5‐yl)methane ( L ^G ) reacts with trivalent lanthanide ions in acetonitrile to yield triple‐stranded dimetallic helicates [Ln₂( L ^G )₃]⁶⁺. ¹H‐NMR Data point to the helicates being the only species formed under stoichiometric conditions and having a time‐averaged D₃ symmetry on the NMR time scale. The photophysical properties of L ^G and its helicates are discussed with respect to the closely related ligands L ^B , L ^E , and their complexes, two ligands devoid of the isothiocyanatophenylethynyl substituent. The quantum yield of the ligand fluorescence is three times smaller compared to L ^E , while that of the Eu^III‐centered luminescence (1.1%) is three times larger. On the other hand, the luminescence of Tb^III is not sensitized by L ^G . This is explained in terms of energy differences between the singlet and triplet states on one hand, and between the 0‐phonon transition of the triplet state and the excited metal ion states on the other. This work demonstrates that bulky substituents in the 4‐position of the pyridine ring do not prevent the formation of triple‐stranded helicates, opening the way for luminescent probes that can easily be coupled to biological materials.     

Asymmetric Hydrogenation with Iridium C,N and N,P Ligand Complexes: Characterization of Dihydride Intermediates with a Coordinated Alkene

Previously elusive iridium dihydride alkene complexes have been identified and characterized by NMR spectroscopy in solution. Reactivity studies demonstrated that these complexes are catalytically competent intermediates. Additional H₂ is required to convert the catalyst‐bound alkene into the hydrogenation product, supporting an Ir^III/Ir^V cycle via an [Ir^III(H)₂(alkene)(H₂)(L)]⁺ intermediate, as originally proposed based on DFT calculations. NMR analyses indicate a reaction pathway proceeding through rapidly equilibrating isomeric dihydride alkene intermediates with a subsequent slow enantioselectivity‐determining step. As in the classical example of asymmetric hydrogenation with rhodium diphosphine catalysts, it is a minor, less stable intermediate that is converted into the major product enantiomer.     

Oxidative addition of aryl halides to iridium(I) complexes. A new arylation reagent

Oxidative addition of aryl halides, ArX, to chlorocarbonylbis(triphenylphos-phine)iridium(I) yields iridium(III) aryl complexes, IrCl(X)(Ar)(CO)(PPh₃)₂. The reactivity of the aryl halide decreases in the order I > Br > C1, and electron-withdrawing substituents in the aryl ring accelerate the reaction. The Ir^III compounds may be utilised as arylating agents.     

Highly Efficient Triplet Photosensitizers: A Systematic Approach to the Application of IrIII Complexes containing Extended Phenanthrolines

A series of Ir^III complexes, based on 1,10‐phenanthroline featuring aryl acetylene chromophores, were prepared and investigated as triplet photosensitizers. The complexes were synthesized by Sonogashira cross‐coupling reactions using a “chemistry‐on‐the‐complex” method. The absorption properties and luminescence lifetimes were successfully tuned by controlling the number and type of light‐harvesting group. Intense UV/Vis absorption was observed for the Ir^III complexes with two light‐harvesting groups at the 3‐ and 8‐positions of the phenanthroline. The asymmetric Ir^III complex (with a triphenylamine (TPA) and a pyrene moiety attached) exhibited the longest lifetime. Red emission was observed for all the complexes in deaerated solutions at room temperature. Their emission at low temperature (77 K) and nanosecond time‐resolved transient difference absorption spectra revealed the origin of their triplet excited states. The singlet‐oxygen (¹O₂) sensitization and triplet‐triplet annihilation (TTA)‐based upconversion were explored. Highly efficient TTA upconversion (Φ_UC=28.1 %) and ¹O₂ sensitization (Φ_Δ=97.0 %) were achieved for the asymmetric Ir^III complex, which showed intense absorption in the visible region (λ_abs=482 nm, ?=50900 m ^?1 cm^?1) and had a long‐lived triplet excited state (53.3 μs at RT).     

2‐(2′‐Pyridyl)‐4,6‐diphenylphosphinine versus 2‐(2′‐Pyridyl)‐4,6‐diphenylpyridine: Synthesis,Characterization, and Reactivity of Cationic RhIII and IrIII Complexes Based on Aromatic Phosphorus Heterocycles

The bidentate P,N hybrid ligand 1 allows access for the first time to novel cationic phosphinine‐based Rh^III and Ir^III complexes, broadening significantly the scope of low‐coordinate aromatic phosphorus heterocycles for potential applications. The coordination chemistry of 1 towards Rh^III and Ir^III was investigated and compared with the analogous 2,2′‐bipyridine derivative, 2‐(2′‐pyridyl)‐4,6‐diphenylpyridine ( 2 ), which showed significant differences. The molecular structures of [RhCl(Cp*)( 1 )]Cl and [IrCl(Cp*)( 1 )]Cl (Cp*=pentamethylcyclopentadienyl) were determined by means of X‐ray diffraction and confirm the mononuclear nature of the λ³‐phosphinine–Rh^III and Ir^III complexes. In contrast, a different reactivity and coordination behavior was found for the nitrogen analogue 2 , especially towards Rh^III as a bimetallic ion pair [RhCl(Cp*)( 2 )]⁺[RhCl₃(Cp*)]^? is formed rather than a mononuclear coordination compound. [RhCl(Cp*)( 1 )]Cl and [IrCl(Cp*)( 1 )]Cl react with water regio‐ and diastereoselectively at the external P?C double bond, leading exclusively to the anti‐addition products [MCl(Cp*)( 1 H ? OH)]Cl as confirmed by X‐ray crystal‐structure determination.     

A Fluorescent Molecular Probe for the Detection of Hydrogen Based on Oxidative Addition Reactions with Crabtree‐Type Hydrogenation Catalysts

A Crabtree‐type Ir^I complex tagged with a fluorescent dye (bodipy) was synthesized. The oxidative addition of H₂ converts the weakly fluorescent Ir^I complex (Φ=0.038) into a highly fluorescent Ir^III species (Φ=0.51). This fluorogenic reaction can be utilized for the detection of H₂ and to probe the oxidative addition step in the catalytic hydrogenation of olefins.