Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò-Büchi reactions.

Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò-Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

Spatiotemporally Controlled Photolabeling of Genetically Unmodified Proteins in Live Cells.

Selective labeling of the protein of interest (POI) in genetically unmodified live cells is crucial for understanding protein functions and kinetics in their natural habitat. In particular, spatiotemporally controlled installation of the labels on a POI under light control without affecting their original activity is in high demand but is a tremendous challenge. Here, we describe a novel ligand-directed photoclick strategy for spatiotemporally controlled labeling of endogenous proteins in live cells. It was realized with a designer labeling reagent skillfully integrating the photochemistries of 2-nitrophenylpropyloxycarbonyl and 3-hydroxymethyl-2-naphthol with an affinity ligand. Highly electrophilic ortho-naphthoquinone methide was photochemically released and underwent a proximity coupling reaction with nucleophilic amino acid residues on the POI in live cells. With fluorescein as a marker, this photoclick strategy enables time-resolved labeling of carbonic anhydrase subtypes localized either on the cell membrane or in the cytoplasm and a discriminable visualization of their metabolic kinetics. Given the versatility underlined by facilely tethering other functional entities (e.g., biotin, a peptide short chain) via acylation or (in cell) Huisgen cycloaddition, this affinity-driven photoclick chemistry opens up enormous opportunities for discovering dynamic functions and mechanistic interrogation of endogenous proteins in live cells.

Repeated atrial arrhythmia induced by cochineal red poisoning: A case report.

BACKGROUND: Cochineal red is an organic compound widely used in food, cosmetics, pharmaceuticals, textiles, and other fields due to its excellent safety profile. Poisoning caused by eating foods containing cochineal red is rare, and repeated atrial arrhythmia due to cochineal red poisoning is even rarer. CASE SUMMARY: An 88-year-old Asian female patient was admitted to hospital due to a disturbance of consciousness. Twelve hours prior to presentation, the patient consumed 12 eggs containing cochineal red over a period of 2 h. At presentation, the patient was in a coma and had a score of 6 on the Glasgow Coma Scale (E2 + VT + M4). The patient's skin and mucous membranes were pink. Electrocardiography (ECG) revealed rapid atrial fibrillation without any signs of ischemia. We prescribed cedilan and fluid replacement for arrhythmia correction. Shortly after admission, the atrial fibrillation corrected to a normal sinus rhythm. On the day 2 of admission, the patient had a sudden atrial flutter accompanied by hemodynamic instability and rapidly declining arterial oxygen saturation between 85% and 90%. The sinus rhythm returned to normal after two electrical cardioversions. Six days after admission, the skin color of the patient returned to normal, and the ECG results were normal. The patient was transferred out of the intensive care unit and eventually discharged after 12 d in hospital. At the 2-mo follow-up visit, the patient was in good health with no recurrence of arrhythmia. CONCLUSION: Although cochineal red is a safe, natural food additive, excessive consumption or occupational exposure can induce cardiac arrhythmias.

Fluorescent Turn-On Probes for Visualizing GPx4 Levels in Live Cells and Predicting Drug Sensitivity.

Glutathione peroxidase 4 (GPx4) is the membrane peroxidase in mammals that is essential for protecting cells against oxidative damage and critical for ferroptosis. However, no live cell probe is currently available to specifically label GPx4. Herein, we report both inhibitory and noninhibitory fluorescent turn-on probes for specific labeling of GPx4 in live cells. With these probes, the GPx4 expression levels and degradation kinetics in live cells could be visualized, and their real-time responses to the cellular selenium availability were revealed. These probes could also potentially serve as staining reagents to predict the sensitivity of GPx4-related ferroptosis drugs. In view of these features, these GPx4-selective probes will offer opportunities for a deeper understanding of GPx4 function in natural habitats and hold great promise for biomedical applications.

Acute respiratory distress syndrome following multiple wasp stings treated with extracorporeal membrane oxygenation: A case report.

BACKGROUND: It is necessary for clinicians to be aware of a rare but possible acute respiratory distress syndrome (ARDS) complication caused by multiple wasp stings. Severe ARDS has a high mortality rate but no specific pharmacotherapies have been identified to date. This case study presents the first case of severe ARDS caused by multiple wasp stings, treated successfully with extracorporeal membrane oxygenation (ECMO). It also emphasizes the effectiveness of early ECMO treatment for severe ARDS with persistent hypoxemia. CASE SUMMARY: A 24-year-old woman was admitted to the emergency department after being stung by more than 10 wasps within a 30-min period, with clinical symptoms of multiple rashes, dizziness, chest tightness, nausea, and vomiting. On the 2nd day of admission, the patient developed progressive dyspnea. The patient was diagnosed with ARDS based on clinical manifestations and lung computed tomography (CT) scan. Because of the progressive dyspnea, the intensive care unit physician performed endotracheal intubation and continued to provide ventilator support, but the patient's respiratory distress worsened, as indicated by the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen. Veno-venous ECMO was initiated for 6 d. On day 7 of admission, ECMO was stopped. On the 11th day of admission, CT scan of the lungs revealed significant reduction of ground-glass opacities and consolidations. After about 2 wk, the patient recovered completely from ARDS and was discharged to home. At the 2-mo follow-up, the patient was in good health with no recurrence of dyspnea nor chest tightness. CONCLUSION: ARDS complication caused by multiple wasp stings may be fatal when mechanical ventilation becomes dangerous due to persistent hypoxemia and despite optimization of ARDS management. We propose that the early implementation of ECMO is a relatively effective treatment, although the evidence is relatively limited.

Light-Controlled Traceless Protein Labeling via Decaging Thio-o-naphthoquinone Methide Chemistry.

We report the molecular design of a novel multifunctional reagent and its application for light-controlled selective protein labeling. This molecule integrates functions of protein-ligand recognition, bioconjugation, ligand cleavage, and photoactivation by merging the photochemistries of 2-nitrophenylpropyloxycarbonyl and 3-hydroxymethyl-2-naphthol with an affinity ligand and fluorescein. Highly electrophilic o-naphthoquinone methide was photochemically released and underwent proximity-driven selective labeling with the protein of interest (e.g., carbonic anhydrases), which retains its native function after labeling.

Defined positive charge patterns created on DNA nanostructures determine cellular uptake efficiency.

We provide an effective method to create DNA nanostructures below 100 nm with defined charge patterns and explore whether the density and location of charges affect the cellular uptake efficiency of nanoparticles (NPs). To avoid spontaneous charge neutralization, the negatively charged polymer nanopatterns were first created by in situ polymerization using photoresponsive monomers on DNA origami. Subsequent irradiation generated positive charges on the immobilized polymers, achieving precise positively charged patterns on the negatively charged DNA surface. Via this method, we have discovered that the positive charges located on the edges of nanostructures facilitate more efficient cellular uptake in comparison to the central counterparts. In addition, the high-density positive charge decoration could also enhance particle penetration into 3D multicellular spheroids. This strategy paves a new way to construct elaborate charge-separated substructures on NP surfaces and holds great promise for a deeper understanding of the influence between the surface charge distribution and nano-bio interactions.

Catalytic Atroposelective Electrophilic Amination of Indoles.

Reported here is the first catalytic atroposelective electrophilic amination of indoles, which delivers functionalized atropochiral N-sulfonyl-3-arylaminoindoles with excellent optical purity. This reaction was furnished by 1,6-nucleophilic addition to p-quinone diimines. Control experiments suggest an ionic mechanism that differs from the radical addition pathway commonly proposed for 1,6-addition to quinones. The origin of 1,6-addition selectivity was investigated through computational studies. Preliminary studies show that the obtained 3-aminoindoles atropisomers exhibit anticancer activities. This method is valuable with respect to enlarging the toolbox for atropochiral amine derivatives.

Chemical Modification for the "Off-/On" Regulation of Enzyme Activity.

Enzymes with excellent catalytic performance play important roles in living organisms. Advances in strategies for enzyme chemical modification have enabled powerful strategies for exploring and manipulating enzyme functions and activities. Based on the development of chemical enzyme modifications, incorporating external stimuli-responsive features-for example, responsivity to light, voltage, magnetic force, pH, temperature, redox activity, and small molecules-into a target enzyme to turn "on" and "off" its activity has attracted much attention. The ability to precisely control enzyme activity using different approaches will greatly expand the chemical biology toolbox for clarification and detection of signal transduction and in vivo enzyme function and significantly promote enzyme-based disease therapy. This review summarizes the methods available for chemical enzyme modification mainly for the off-/on control of enzyme activity and particularly highlights the recent progress regarding the applications of this strategy.

Intermolecular Vicinal Diaminative Assembly of Tetrahydroquinoxalines via Metal-free Oxidative [4 + 2] Cycloaddition Strategy.

Reported herein is the first metal-free oxidative [4 + 2] coupling of o-phenylenediamines with various alkenes. Differing from the known strategy that hinged on reactive π-allyl Pd intermediates from restrained allylic alcohol/acetate and diene substrates, this metal-free method features easy accessibility of starting materials, step economy, benign reaction conditions, and more importantly broad C-C double bonds (styrenes, vinyl (thio)ethers, benzofurans, indoles) with diastereospecificities. Mechanistic studies suggest the intermediacy of the benzoquinone diimides, a class of useful but yet underexploited synthons. Of note, they efficiently furnished functionalized tetrahydroquinoxalines and complement the well-studied alkene vicinal diamination typically toward acyclic diamine derivatives.

Synergistic Catalysis-Enabled Thia-Aza-Prins Cyclization with DMSO and Disulfides: Entry to Sulfenylated 1,3-Oxazinanes and Oxazolidines.

A novel synergistically catalyzed thia-aza-Prins cyclization of alkenylamines with disulfides is reported, rendering the first synthesis of sulfenylated 1,3-oxazinanes and oxazolidines in good to high yields. Importantly, DMSO serves simultaneously as a reaction medium and a surrogate for formaldehyde. Mechanistic studies provide evidence that actions of CuBr2 and in situ formed sulfinic acids as a Lewis acid and Brønsted acid catalyst, respectively, synergistically catalyze these cyclization processes.

Iron-Catalyzed Regiospecific Intermolecular Radical Cyclization of Anilines: Strategy for Assembly of 2,2-Disubstituted Indolines.

The first regiospecific catalytic intermolecular assembly of 2,2-disubstituted indolines has been developed. This protocol is based on a ligand and directing group free, iron-catalyzed radical [3 + 2] process, allowing efficient coupling of different N-sulfonylanilines with various α-substituted styrenes. Preliminary mechanistic studies elucidated the radical mechanism involving a reactive and versatile anilino radical and the importance of iron complex as a Lewis acid, rendering both the reactivity and regiospecificity of this transformation.