Reversing Signs of Parkinsonism in a Cell Model Using Mitochondria-Targeted Organoiridium Catalysis.

We report the application of organoiridium complexes as catalytic agents for the detoxification of biogenic reactive aldehyde species (RASP), which are implicated in the pathogenesis of neurodegenerative disorders. We show that Ir complexes functionalized with phosphonium cations localize selectively in the mitochondria and have better cellular retention compared to that of their parent Ir species. In a cell model for Parkinsonism, the mitochondria-targeted iridium catalysts exhibited superior cell protecting abilities and longer-lasting effects (up to 6 d) than conventional RASP scavengers, which failed to be effective beyond 24 h.

A ratiometric substrate for rapid evaluation of transfer hydrogenation efficiency in solution.

A cyclometalated iridium(III) complex bearing a self-immolative quinolinium moiety was developed as a ratiometric substrate for transfer hydrogenation studies. This photoluminescent probe allowed the rapid screening of a variety of Ir catalysts using a microplate reader, offering a convenient method to assess activity using a minimum amount of catalyst sample.

Lewis acid-driven self-assembly of diiridium macrocyclic catalysts imparts substrate selectivity and glutathione tolerance.

Molecular inorganic catalysts (MICs) tend to have solvent-exposed metal centers that lack substrate specificity and are easily inhibited by biological nucleophiles. Unfortunately, these limitations exclude many MICs from being considered for applications. To overcome this challenge, a strategy to spatially confine MICs using Lewis acid-driven self-assembly is presented.

Variations in Intracellular Organometallic Reaction Frequency Captured by Single-Molecule Fluorescence Microscopy.

Studies of organometallic reactions in living cells commonly rely on ensemble-averaged measurements, which can obscure the detection of reaction dynamics or location-specific behavior. This information is necessary to guide the design of bioorthogonal catalysts with improved biocompatibility, activity, and selectivity. By leveraging the high spatial and temporal resolution of single-molecule fluorescence microscopy, we have successfully captured single-molecule events promoted by Ru complexes inside live A549 human lung cells.

Organoiridium Complexes Enhance Cellular Defense Against Reactive Aldehydes Species.

Although reactive aldehyde species (RASP) are associated with the pathogenesis of many major diseases, there are currently no clinically approved treatments for RASP overload. Conventional aldehyde detox agents are stoichiometric reactants that get consumed upon reacting with their biological targets, which limits their therapeutic efficiency. To achieve longer-lasting detoxification effects, small-molecule intracellular metal catalysts (SIMCats) were used to protect cells by converting RASP into non-toxic alcohols.

Taming glutathione potentiates metallodrug action.

Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations.

Customizing Polymers by Controlling Cation Switching Dynamics in Non-Living Polymerization.

Controlling the chain growth process in non-living polymerization reactions is difficult because chain termination typically occurs faster than the time it takes to apply an external trigger. To overcome this limitation, we have developed a strategy to regulate non-living polymerizations by exploiting the chemical equilibria between a metal catalyst and secondary metal cations. We have prepared two nickel phenoxyphosphine-polyethylene glycol variants, one with 2-methoxyphenyl () and another with 2,6-dimethoxyphenyl () phosphine substituents.

Fluorescent half-sandwich iridium picolinamidate complexes for in-cell visualization.

In this work, we report on the development of fluorescent half-sandwich iridium complexes using a fluorophore attachment strategy. These constructs consist of pentamethylcyclopentadienyl (Cp*) iridium units ligated by picolinamidate donors conjugated to green-emitting boron-dipyrromethene (bodipy) dyes. Reaction studies in HO/THF mixtures showed that the fluorescent Ir complexes were active as catalysts for transfer hydrogenation, with activities similar to that of their non-fluorescent counterparts.

Rigidifying Cation-Tunable Nickel Catalysts Increases Activity and Polar Monomer Incorporation in Ethylene and Methyl Acrylate Copolymerization.

In this study, we synthesized and characterized two nickel complexes featuring conformationally rigid bisphosphine mono-oxide ligands, where one has an -methoxyphenyl () and the other has an -(2-methoxyethoxy)phenyl () substituent on the P═O moiety. We performed metal binding studies using and found that its reaction with Li and Na most likely produced 1:1 and 1:1/2:1 nickel:alkali species in solution, respectively. The nickel complexes were competent catalysts for ethylene homopolymerization and copolymerization, with activities up to 3.

Tools and Methods for Investigating Synthetic Metal-Catalyzed Reactions in Living Cells.

Although abiotic catalysts are capable of promoting numerous new-to-nature reactions, only a small subset has so far been successfully integrated into living systems. Research in intracellular catalysis requires an interdisciplinary approach that takes advantage of both chemical and biological tools as well as state-of-the-art instrumentations. In this perspective, we will focus on the techniques that have made studying metal-catalyzed reactions in cells possible using representative examples from the literature.

Organoiridium-quinone conjugates for facile hydrogen peroxide generation.

An organoiridium complex bearing a quinone moiety was shown to significantly accelerate the rate of HO formation in the presence of air and sodium formate at low catalyst concentrations. This reaction is proposed to operate through a synergistic mechanism involving transfer hydrogenation catalysis and radical chemistry. Our bifunctional iridium complex could potentially be used in anti-cancer chemotherapy or other applications requiring rapid generation of reactive oxygen species.

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.

Accelerating ethylene polymerization using secondary metal ions in tetrahydrofuran.

We have prepared a new series of nickel phosphine phosphonate ester complexes that feature two metal-chelating polyethylene glycol (PEG) side arms. Metal binding and reactivity studies in polar solvents showed that they readily coordinate external cations, including alkali (Li, Na, K), alkaline (Mg, Ca), transition (Sc, Co, Zn), post-transition (Ga), and lanthanide (La) metals. Although olefin polymerization reactions are typically performed in non-polar solvents, which cannot solubilize +2 and +3 metal cations, we discovered that our nickel catalysts could promote ethylene polymerization in neat tetrahydrofuran.

Evaluation of dicopper azacryptand complexes in aqueous CuAAC reactions and their tolerance toward biological thiols.

A series of dicopper azacryptand complexes was evaluated in copper-catalysed azide-alkyne cycloaddition (CuAAC) in water at 37 °C. It was found that they showed high activity at concentrations as low as 5 μM. These dinuclear catalysts were more susceptible toward inhibition by cysteine rather than glutathione under the conditions tested.

Intracellular Chemistry: Integrating Molecular Inorganic Catalysts with Living Systems.

This concept article focuses on the rapid growth of intracellular chemistry dedicated to the integration of small-molecule metal catalysts with living cells and organisms. Although biological systems contain a plethora of biomolecules that can deactivate inorganic species, researchers have shown that small-molecule metal catalysts could be engineered to operate in heterogeneous aqueous environments. Synthetic intracellular reactions have recently been reported for olefin hydrogenation, hydrolysis/oxidative cleavage, azide-alkyne cycloaddition, allylcarbamate cleavage, C-C bond cross coupling, and transfer hydrogenation.

Intracellular Transfer Hydrogenation Mediated by Unprotected Organoiridium Catalysts.

In the present work, we show for the first time that the conversion of aldehydes to alcohols can be achieved using "unprotected" iridium transfer hydrogenation catalysts inside living cells. The reactions were observed in real time by confocal fluorescence microscopy using a Bodipy fluorogenic substrate. We propose that the reduced cofactor nicotinamide adenine dinucleotide (NADH) is a possible hydride source inside the cell based on studies using pyruvate as a cellular redox modulator.

Innocent But Deadly: Nontoxic Organoiridium Catalysts Promote Selective Cancer Cell Death.

We demonstrate that nontoxic organoiridum complexes can selectively chemosensitize cancer cells toward platinum antiproliferative agents. Treatment of human cancer cells (breast, colon, eye/retina, head/neck, lung, ovary, and blood) with the iridium chemosensitizers led to lowering of the 50 % growth inhibition concentration (IC ) of the Pt drug carboplatin by up to ∼30-50 %. Interestingly, non-cancer cells were mostly resistant to the chemosensitizing effects of the iridium complexes.

Insights into the anti-angiogenic properties of phosphaplatins.

Phosphaplatins are platinum-based antitumor compounds that, unlike other clinically utilized platinum drugs (i.e. cisplatin, carboplatin, and oxaliplatin), appear to target proteins rather than DNA.

Fine-Tuning Nickel Phenoxyimine Olefin Polymerization Catalysts: Performance Boosting by Alkali Cations.

To gain a better understanding of the influence of cationic additives on coordination-insertion polymerization and to leverage this knowledge in the construction of enhanced olefin polymerization catalysts, we have synthesized a new family of nickel phenoxyimine-polyethylene glycol complexes (NiL0, NiL2-NiL4) that form discrete molecular species with alkali metal ions (M(+) = Li(+), Na(+), K(+)). Metal binding titration studies and structural characterization by X-ray crystallography provide evidence for the self-assembly of both 1:1 and 2:1 NiL:M(+) species in solution, except for NiL4/Na(+) which form only the 1:1 complex. It was found that upon treatment with a phosphine scavenger, these NiL complexes are active catalysts for ethylene polymerization.

Light-induced N₂O production from a non-heme iron-nitrosyl dimer.

Two non-heme iron-nitrosyl species, [Fe2(N-Et-HPTB)(O2CPh)(NO)2](BF4)2 (1a) and [Fe2(N-Et-HPTB)(DMF)2(NO)(OH)](BF4)3 (2a), are characterized by FTIR and resonance Raman spectroscopy. Binding of NO is reversible in both complexes, which are prone to NO photolysis under visible light illumination. Photoproduction of N2O occurs in high yield for 1a but not 2a.

Spectral studies of a Cr(PNP)-MAO system for selective ethylene trimerization catalysis: searching for the active species.

Variable temperature spectroscopic, kinetic, and chemical studies were performed on a soluble CrCl(PNP) (PNP = bis(diarylphosphino)alkylamine) ethylene trimerization precatalyst to map out its methylaluminoxane (MAO) activation sequence. These studies indicate that treatment of CrCl(PNP) with MAO leads to first replacement of chlorides with alkyl groups, followed by alkyl abstraction, and then reduction to lower-valent species. Reactivity studies demonstrate that the majority of the chromium species detected is not catalytically active.

Mechanistic Studies of Ethylene and α-Olefin Co-oligomerization Catalyzed by Chromium-PNP Complexes.

To explore the possibility of producing a narrow distribution of mid- to long-chain hydrocarbons from ethylene as a chemical feedstock, co-oligomerization of ethylene and linear α-olefins (LAOs) was investigated, using a previously reported chromium complex, [CrCl(3)(PNP(OMe))] (1, where PNP(OMe) = N,N-bis(bis(o-methoxyphenyl)phosphino)methylamine). Activation of 1 by treatment with modified methylaluminoxane (MMAO) in the presence of ethylene and 1-hexene afforded mostly C(6) and C(10) alkene products. The identities of the C(10) isomers, assigned by detailed gas chromatographic and mass spectrometric analyses, strongly support a mechanism that involves five- and seven-membered metallacyclic intermediates comprising of ethylene and LAO units.

A C2-symmetric, basic Fe(III) carboxylate complex derived from a novel triptycene-based chelating carboxylate ligand.

A triptycene-based bis(benzoxazole) diacid ligand H(2)L2(Ph4) bearing sterically encumbering groups was synthesized. Treatment of H(2)L2(Ph4) with Fe(OTf)(3) afforded a C(2)-symmetric trinuclear iron(III) complex, [NaFe(3)(L2(Ph4))(2)(μ(3)-O)(μ-O(2)CCPh(3))(2)(H(2)O)(3)](OTf)(2) (8). The triiron core of this complex adopts the well known "basic iron acetate" structure where the heteroleptic carboxylates, comprising two Ph(3)CCO(2)(-) and two (L2(Ph4))(2-) ligands, donate the six carboxylate bridges.

Evaluating the identity and diiron core transformations of a (μ-oxo)diiron(III) complex supported by electron-rich tris(pyridyl-2-methyl)amine ligands.

The composition of a (μ-oxo)diiron(III) complex coordinated by tris[(3,5-dimethyl-4-methoxy)pyridyl-2-methyl]amine (R(3)TPA) ligands was investigated. Characterization using a variety of spectroscopic methods and X-ray crystallography indicated that the reaction of iron(III) perchlorate, sodium hydroxide, and R(3)TPA affords [Fe(2)(μ-O)(μ-OH)(R(3)TPA)(2)](ClO(4))(3) (2) rather than the previously reported species [Fe(2)(μ-O)(OH)(H(2)O)(R(3)TPA)(2)](ClO(4))(3) (1). Facile conversion of the (μ-oxo)(μ-hydroxo)diiron(III) core of 2 to the (μ-oxo)(hydroxo)(aqua)diiron(III) core of 1 occurs in the presence of water and at low temperature.

Evolution of strategies to prepare synthetic mimics of carboxylate-bridged diiron protein active sites.

We present a comprehensive review of research conducted in our laboratory in pursuit of the long-term goal of reproducing the structures and reactivity of carboxylate-bridged diiron centers used in biology to activate dioxygen for the conversion of hydrocarbons to alcohols and related products. This article describes the evolution of strategies devised to achieve these goals and illustrates the challenges in getting there. Particular emphasis is placed on controlling the geometry and coordination environment of the diiron core, preventing formation of polynuclear iron clusters, maintaining the structural integrity of model complexes during reactions with dioxygen, and tuning the ligand framework to stabilize desired oxygenated diiron species.