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. It was shown that SIMCats were significantly more effective in lowering cell death from the treatment with 4-hydroxynon-2-enal than aldehyde scavengers over a 72 h period. Studies revealed that SIMCats reduced the aldehyde accumulation in cells exposed to the known RASP inducer arsenic trioxide. This work demonstrates that SIMCats offer unique benefits over stochiometric agents, potentially providing new ways to combat diseases with greater selectivity and efficiency than existing approaches.

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 H2O/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. The iridium complexes were taken up by NIH-3T3 mouse fibroblast cells, with 50% inhibition concentrations ranging from ~20-70 µM after exposure for 3 h. Visualization of the bodipy-functionalized Ir complexes in cells using fluorescence microscopy revealed that they were localized in the mitochondria and lysosome but not the nucleus. These results indicate that our fluorescent iridium complexes could be useful for future biological studies requiring intracellular catalyst tracking.

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. Other promising targets for new biocompatible reaction discovery will also be discussed, with a special emphasis on how such innovations could lead to the development of novel technologies and chemical tools.

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. We expect that this biocompatible reductive chemistry will be broadly useful to practitioners working at the interface of chemistry and the life sciences.

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 (IC50 ) 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. Cell culture studies indicate that cancer cells that were administered with Ir show significantly higher reactive oxygen species concentrations as well as NAD+ /NADH ratios (oxidized vs. reduced nicotinamide adenine dinucleotide) than Ir-treated non-cancer cells. These biochemical changes are consistent with a catalytic transfer hydrogenation cycle involving the formation of iridium-hydride species from the reaction of the iridium catalysts with NADH and subsequent oxidation in air to generate hydrogen peroxide.

Genetic factors that regulate the attenuation of the general stress response of yeast.

The general stress response of yeast involves the induction of approximately 200 genes in response to any one of several stresses. These genes are activated by Msn2 and repressed by the Srb10 kinase, a member of the mediator complex. Normally, Msn2 is exported from the nucleus, and Srb10 represses STRE gene expression. Under stress, Msn2 relocalizes to the nucleus and, with the relief of Srb10 repression, activates transcription. The stress response is rapid, but quickly attenuated. We show here that this attenuation is due to a nuclear-dependent degradation of Msn2. Msn2 rapidly disappeared from cells after heat or osmotic shock. This disappearance was not due to a change in MSN2 RNA levels, which remain constant during stress. Pulse-chase experiments confirmed the stress-dependent Msn2 degradation. The levels of Msn2 were significantly reduced in msn5 deletion cells that have been shown to constitutively retain Msn2 in the nucleus. The degradation was Srb10-dependent; Msn2 was not degraded in an srb10 deletion mutant. An Msn2 internal deletion mutant was insensitive to Srb10 repression, but was degraded by the Srb10-dependent mechanism. Thus, this mutation uncoupled Srb10 repression from degradation.