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Remarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative. [ABSTRACT FROM AUTHOR]

A novel one‐pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α‐diphenyl‐2‐pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)‐enantiomer and (2S,3S)‐enantiomer in solution, achieving a one‐pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)‐carprofen, (R,S)‐indoprofen, and (R,S)‐indobufen. The one‐pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization‐induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy. [ABSTRACT FROM AUTHOR]

Many biological processes are regulated through dynamic protein phosphorylation. Monitoring disease‐relevant phosphorylation events in circulating biofluids is highly appealing but also technically challenging. We introduce here a functionally tunable material and a strategy, extracellular vesicles to phosphoproteins (EVTOP), which achieves one‐pot extracellular vesicles (EVs) isolation, extraction, and digestion of EV proteins, and enrichment of phosphopeptides, with only a trace amount of starting biofluids. EVs are efficiently isolated by magnetic beads functionalized with TiIV ions and a membrane‐penetrating peptide, octa‐arginine R8+, which also provides the hydrophilic surface to retain EV proteins during lysis. Subsequent on‐bead digestion concurrently converts EVTOP to TiIV ion‐only surface for efficient enrichment of phosphopeptides for phosphoproteomic analyses. The streamlined, ultra‐sensitive platform enabled us to quantify 500 unique EV phosphopeptides with only a few μL of plasma and over 1200 phosphopeptides with 100 μL of cerebrospinal fluid (CSF). We explored its clinical application of monitoring the outcome of chemotherapy of primary central nervous system lymphoma (PCNSL) patients with a small volume of CSF, presenting a powerful tool for broad clinical applications. [ABSTRACT FROM AUTHOR]

The synergistic effect of bimetallic heterogeneous catalysis in the reaction of nitrate reduction to nitrogen has been widely discussed, but it is still not clear how this effect works at the atomic scale, hindering the rational design of high‐performance catalysts. Here, for the first time, 2D phosphorene was used as a giant P ligand to confine high‐density PdCu dual‐atom to form a unique PdCuP4 coordination structure, and this catalyst achieves 96.3 % NO3− removal rate and 95.2 % N2 selectivity. In situ characterization combined with density functional theory (DFT) calculations show that the PdCu dual‐atom form covalent‐like bonds with adjacent P atoms, reducing the adsorption energy of the reactants. The synergistic effect of PdCu dual‐atom promotes the breaking of N−O bond, and the short bond length of ≈3 Å between PdCu atoms accelerates the transfer of NO2−, and eventually the two Pd−N adjacent to the surface of Pd rapidly combine to form N2. [ABSTRACT FROM AUTHOR]

A Journal of the German Chemical Society AngewandteChemie www. angewandte. org International Edition 2024– 63/ 22 A. bifunctional chiral agent … … ( BCA) strategy opens a new window to develop essential enantiomerically pure pharmaceutical products. In their Communication ( e202402886), Weiwei Tang et al. report a novel crystallization- induced deracemization method using BCA that demonstrates the dual functions of cocrystallization and catalytic racemization. This BCA strategy could address the incompatibility between cocrystallization and racemization reaction conditions. [Extracted from the article]

Despite recent interests in developing lysine‐targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell‐active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde‐based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR‐ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug‐resistant ABL mutations. Among them, the salicylaldehyde‐containing A5 is the first‐ever reversible covalent ABL inhibitor that possessed time‐dependent ABL inhibition with prolonged residence time and few cellular off‐targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome. [ABSTRACT FROM AUTHOR]

The inhalation of atmospheric particles is deleterious to human health. However, as a complex mixture, tracing the behaviors of multiple components from real aerosol particles is crucial but unachievable by the existing methods. Here, taking advantage of the intrinsic fingerprints of elemental carbon (EC) and organic carbon (OC) in carbonaceous aerosol (CA) upon laser irradiation, we proposed a label‐free mass spectrometry imaging method to visualize and quantify the deposition, translocation and component variation of CA in organs. With this method, the heterogeneous deposition, clearance and release behavior of CA in lung, that more OC was released in parenchyma and OC was cleared faster than EC, was observed. The translocation of CA to extrapulmonary organs including kidney, liver, spleen and even brain was also verified and quantified. By comparing the ratio of OC to EC, an organ‐specific release behavior of OC from CA during circulation was revealed. In orthotopic lung and liver tumor, OC was found to penetrate more into tumor foci than EC. This technique provides deeper information for understanding the systemic health effects of aerosol particles. [ABSTRACT FROM AUTHOR]

Mitochondria and nucleus play crucial roles during cell apoptosis process. In this work, a unique fluorescent probe capable of reversible migration between mitochondria and nucleus, as well as detection of cell viability in a dual‐color mode is presented. The dual‐color probe targets mitochondria in healthy cells, to form aggregates with deep‐red emission. It migrates into nucleus and binds to DNA to form monomers with green fluorescence during apoptosis. Interestingly, the migration is reversible dependent on cell viability, which enables the dynamic visualization of apoptosis process. With the probe, mitochondria and nucleus can be visualized in dual colors during apoptosis, and the cell viability could be monitored by the emission color and localization of the probe. Visualizing cell viability: A fluorescent probe capable of reversible migration between mitochondria and nucleus dependent on cell viability and labelling the two organelles in dual colors has been developed. With the probe, mitochondria and nucleus can be visualized in dual emission channels, and cell viability could be evaluated by intracellular emission color and probe localization. [ABSTRACT FROM AUTHOR]

Despite recent interests in developing lysine‐targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell‐active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde‐based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR‐ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug‐resistant ABL mutations. Among them, the salicylaldehyde‐containing A5 is the first‐ever reversible covalent ABL inhibitor that possessed time‐dependent ABL inhibition with prolonged residence time and few cellular off‐targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome. [ABSTRACT FROM AUTHOR]

Inside Back Cover: Mass Spectrometry Imaging Reveals In Situ Behaviors of Multiple Components in Aerosol Particles (Angew. Keywords: cancer; carbonaceous aerosol; elemental carbon; mass spectrometry imaging; organic carbon EN cancer carbonaceous aerosol elemental carbon mass spectrometry imaging organic carbon 23463 23463 1 10/13/21 20211018 NES 211018 B A novel mass spectrometry imaging b strategy to trace and quantify carbonaceous particles in situ is reported by Jie Sun, Caiqiao Xiong, Zongxiu Nie et al. in their Research Article on page 23225. Cancer, carbonaceous aerosol, elemental carbon, mass spectrometry imaging, organic carbon. [Extracted from the article]

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine‐reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell‐active TCIs are however available. We report herein lysine‐reactive activity‐based probes (ABPs; 2–14) based on the chemistry of aryl fluorosulfates (ArOSO2F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase‐binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X‐ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX‐680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine‐reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine‐reactive ArOSO2F‐based TCIs. [ABSTRACT FROM AUTHOR]

Manipulating the backbone of small molecule acceptors (SMAs) is of particular importance in developing efficient organic solar cells (OSCs). The common design is constructing 2‐arm SMAs with linear or curved backbones. Herein, we report an acceptor 4A‐DFIC with a 4‐arm backbone unexpectedly generated in the reaction of an electron‐rich aromatic diamine and hexaketocyclohexane. Single‐crystal X‐ray diffraction analysis indicates the rigid and twisted molecular plane and the effective molecular stacking of 4A‐DFIC in solid state. 4A‐DFIC shows a low band gap of 1.40 eV and excellent light‐harvesting capability from visible to near‐infrared region. Binary and ternary OSCs based on 4A‐DFIC gave power conversion efficiencies (PCEs) of 15.76 % and 18.60 % (certified 18.1 %), respectively, which are the highest PCEs for multi‐arm SMA‐based OSCs to date. [ABSTRACT FROM AUTHOR]

Chemically prepared λ-MnO2 has not been intensively studied as a material for metal-air batteries, fuel cells, or supercapacitors because of their relatively poor electrochemical properties compared to α- and δ-MnO2. Herein, through the electrochemical removal of lithium from LiMn2O4, highly crystalline λ-MnO2 was prepared as an efficient electrocatalyst for the oxygen reduction reaction (ORR). The ORR activity of the material was further improved by introducing oxygen vacancies (OVs) that could be achieved by increasing the calcination temperature during LiMn2O4 synthesis; a concentration of oxygen vacancies in LiMn2O4 could be characterized by its voltage profile as the cathode in a lithiun-metal half-cell. λ-MnO2− z prepared with the highest OV exhibited the highest diffusion-limited ORR current (5.5 mA cm−2) among a series of λ-MnO2− z electrocatalysts. Furthermore, the number of transferred electrons ( n) involved in the ORR was >3.8, indicating a dominant quasi-4-electron pathway. Interestingly, the catalytic performances of the samples were not a function of their surface areas, and instead depended on the concentration of OVs, indicating enhancement in the intrinsic catalytic activity of λ-MnO2 by the generation of OVs. This study demonstrates that differences in the electrochemical behavior of λ-MnO2 depend on the preparation method and provides a mechanism for a unique catalytic behavior of cubic λ-MnO2. [ABSTRACT FROM AUTHOR]

Developing new optimized bifunctional photocatalyst is of great significant for achieving the high‐performance photo‐assisted Li‐O2 batteries. Herein, a novel bifunctional photo‐assisted Li‐O2 system is constructed by using siloxene nanosheets with ultra‐large size and few‐layers due to its superior light harvesting, semiconductor characteristic, and low recombination rate. An ultra‐low charge potential of 1.90 V and ultra‐high discharge of 3.51 V have been obtained due to the introduction of this bifunctional photocatalyst into Li‐O2 batteries, and these results have realized the round‐trip efficiency up to 185 %. In addition, this photo‐assisted Li‐O2 batteries exhibits a high rate (129 % round‐trip efficiency at 1 mA cm−2), a prolonged cycling life with 92 % efficiency retention after 100 cycles, and the highly reversible capacity of 1170 mAh g−1 at 0.75 mA cm−2. This work will open the vigorous opportunity for high‐efficiency utilization of solar energy into electric system. [ABSTRACT FROM AUTHOR]

Understanding the complex interplay among gasotransmitters is of great significance but remains technically challenging. In this study, we present the design and synthesis of a dually responsive BOD‐NH‐SC reporter for probing the dynamic and alternating existence of NO and H2S in living cells. This designed reporter can repeatedly cycle S‐nitrosation and transnitrosation reactions when successively treated with NO and H2S, thus affording the interchange of NIR fluorescence at 645 nm (NO) and NIR II fluorescence at 936 nm (H2S). In light of this unique fluorescence alternation between two colors, we synthesized water‐soluble BOD‐NH‐SC dots to visualize the intracellular dynamics of NO and H2S. These molecular probes thus provide a toolbox to elucidate the interplaying roles of NO and H2S in the complex interaction networks of various signal transduction pathways. [ABSTRACT FROM AUTHOR]

Metal–organic framework cathodes usually exhibit low capacity and poor electrochemical performance for Li‐ion storage owing to intrinsic low conductivity and inferior redox activity. Now a redox‐active 2D copper–benzoquinoid (Cu‐THQ) MOF has been synthesized by a simple solvothermal method. The abundant porosity and intrinsic redox character endow the 2D Cu‐THQ MOF with promising electrochemical activity. Superior performance is achieved as a Li‐ion battery cathode with a high reversible capacity (387 mA h g−1), large specific energy density (775 Wh kg−1), and good cycling stability. The reaction mechanism is unveiled by comprehensive spectroscopic techniques: a three‐electron redox reaction per coordination unit and one‐electron redox reaction per copper ion mechanism is demonstrated. This elucidatory understanding sheds new light on future rational design of high‐performance MOF‐based cathode materials for efficient energy storage and conversion. [ABSTRACT FROM AUTHOR]

A conjugated copper(II) catecholate based metal–organic framework (namely Cu‐DBC) was prepared using a D2‐symmetric redox‐active ligand in a copper bis(dihydroxy) coordination geometry. The π‐d conjugated framework exhibits typical semiconducting behavior with a high electrical conductivity of ca. 1.0 S m−1 at room temperature. Benefiting from the good electrical conductivity and the excellent redox reversibility of both ligand and copper centers, Cu‐DBC electrode features superior capacitor performances with gravimetric capacitance up to 479 F g−1 at a discharge rate of 0.2 A g−1. Moreover, the symmetric solid‐state supercapacitor of Cu‐DBC exhibits high areal (879 mF cm−2) and volumetric (22 F cm−3) capacitances, as well as good rate capability. These metrics are superior to most reported MOF‐based supercapacitors, demonstrating promising applications in energy‐storage devices. [ABSTRACT FROM AUTHOR]