Carbon monoxide is a member of the gasotransmitter family, which also includes NO and H(2)S, and has been implicated in a variety of pathological and physiological conditions. Whereas exogenous therapeutic additions of CO to tissues and whole animals have been well-studied, the real-time spatial and temporal tracking of CO at the cellular level remains an open challenge. Here we report a new type of turn-on fluorescent probe for selective CO detection based on palladium-mediated carbonylation reactivity. CO Probe 1 (COP-1) is capable of detecting CO both in aqueous buffer and in live cells with high selectivity over a range of biologically relevant reactive small molecules, providing a potentially powerful approach for interrogating its chemistry in biological systems.

Reactive oxygen species (ROS) play important roles in the development and progression of cancer and other diseases, motivating the development of translatable technologies for biological ROS imaging. Here we report Peroxy-Caged-[18F]Fluorodeoxy thymidine-1 (PC-FLT-1), an oxidatively immolative positron emission tomography (PET) probe for H2O2 detection. PC-FLT-1 reacts with H2O2 to generate [18F]FLT, allowing its peroxide-dependent uptake and retention in proliferating cells. The relative uptake of PC-FLT-1 was evaluated using H2O2-treated UOK262 renal carcinoma cells and a paraquat-induced oxidative stress cell model, demonstrating ROS-dependent tracer accumulation. The data suggest that PC-FLT-1 possesses promising characteristics for translatable ROS detection and provide a general approach to PET imaging that can be expanded to the in vivo study of other biologically relevant analytes.

The mechanism of the tert-butylhydroperoxide-mediated, Pd(quinox)-catalyzed Wacker-type oxidation was investigated to evaluate the hypothesis that a selective catalyst-controlled oxidation could be achieved by rendering the palladium coordinatively saturated using a bidentate amine ligand. The unique role of the quinox ligand framework was probed via systematic ligand modifications. The modified ligands were evaluated through quantitative Hammett analysis, which supports a “push-pull” relationship between the electronically asymmetric quinoline and oxazoline ligand modules.

Utilizing the rapidly synthesized Quinox ligand and commercially available aqueous TBHP, a Wacker-type oxidation has been developed, which efficiently converts the traditionally challenging substrate class of protected allylic alcohols to the corresponding acyloin products. Additionally, the catalytic system is general for several other substrate classes, converting terminal olefins to methyl ketones, with short reaction times. The system is scalable (20 mmol) and can be performed with a reduced catalyst loading of 1 mol%. Enantioenriched substrates undergo oxidation with complete retention of enantiomeric excess.

The transcription factor Nrf2 and its downstream target heme oxygenase-1 (HO-1) are essential protective systems against oxidative stress and inflammation. The products of HO-1 enzymatic activity, biliverdin and carbon monoxide (CO), actively contribute to this protection, suggesting that exploitation of these cellular systems may offer new therapeutic avenues in a variety of diseases. Starting from a CO-releasing compound and a chemical scaffold exhibiting electrophilic characteristics (esters of fumaric acid), we report the synthesis of hybrid molecules that simultaneously activate Nrf2 and liberate CO. These hybrid compounds, which we termed "HYCOs", release CO to myoglobin and activate the CO-sensitive fluorescent probe COP-1, while also potently inducing nuclear accumulation of Nrf2 and HO-1 expression and activity in different cell types. Thus, we provide here the first example of a new class of pharmacologically active molecules that target the HO-1 pathway by combining an Nrf2 activator coordinated to a CO-releasing group.

Ethylene is an important plant hormone that is involved in a variety of developmental processes including agriculturally important ripening of certain fruits. Owing to its significant roles, a number of approaches have previously been developed to detect ethylene via molecular interactions. However, there are no current approaches for detection that are selective via a discrete homogeneous molecular interaction. Here we report two profluorescent chemodosimeters for the selective detection of the plant hormone ethylene. The approach consists of a BODIPY fluorophore with a pendant ruthenium recognition element based on a Hoveyda–Grubbs second generation catalysts. A marked increase in fluorescence is observed upon exposure to ethylene and selectivity is observed for ethylene over other alkenes, providing a unique approach toward ethylene detection. Imaging in live cells demonstrated that ethylene could be detected from multiple relevant sources.

Terminal alkene substrates can be converted to methyl ketone products via a palladium‐catalyzed process known as the Wacker oxidation. This process has found widespread application in targeted synthesis, since alkene substrates are easily accessed and unreactive under diverse reaction conditions substrates and the resultant carbonyl products are common precursors for diverse synthetic manipulations. This chapter covers the application of the Wacker oxidation and variations of the Wacker oxidation to various types of alkene substrates. The literature covered spans the inception of the reaction in 1959 through November 2012. A discussion of the current mechanistic understanding is presented, emphasizing considerations that are relevant to synthetic application, including how the nature of the alkene substrate and nucleophiles other than water are proposed to influence the mechanistic pathways and ultimately the product distribution. The “Scope and Limitations” section is separated into discussions relating to functional group tolerance, the influence of heteroatoms proximal to the alkene substrate, and Wacker‐type oxidations that do not result in carbonyl products, such as cyclization reactions and aza‐Wacker reactions. Select applications of the Wacker oxidation in total synthesis are presented, as well as a comparison to other methods and examples of experimental conditions.

Carbon monoxide (CO) is an emerging gasotransmitter and reactive carbon species with broad anti-inflammatory, cytoprotective, and neurotransmitter functions along with therapeutic potential for the treatment of cardiovascular diseases. The study of CO chemistry in biology and medicine relative to other prominent gasotransmitters such as NO and H2S remains challenging, in large part due to limitations in available tools for the direct visualization of this transient and freely diffusing small molecule in complex living systems. Here we report a ligand-directed activity-based sensing (ABS) approach to CO detection through palladium-mediated carbonylation chemistry. Specifically, the design and synthesis of a series of ABS probes with systematic alterations in the palladium-ligand environment (e.g., sp3-S, sp3-N, sp2-N) establish structureactivity relationships for palladacycles to confer selective reactivity with CO under physiological conditions. These fundamental studies led to the development of an optimized probe, termed Carbon Monoxide Probe-3 Ester Pyridine (COP3E-Py), which enables imaging of CO release in live cell and brain settings, including monitoring of endogenous CO production that triggers presynaptic dopamine release in fly brains. This work provides a unique tool for studying CO in living systems and establishes the utility of a synthetic methods approach to activity-based sensing using principles of organometallic chemistry File list (5) download file view on ChemRxiv CJC COP CO Probes Main Text.pdf (5.60 MiB) download file view on ChemRxiv CJC COP CO Probes SI.pdf (2.77 MiB) download file view on ChemRxiv COP-1-PY.cif (26.99 KiB) download file view on ChemRxiv COP-1.cif (25.25 KiB) download file view on ChemRxiv COP-1'.cif (23.98 KiB)