The difluoroamino (NF2) group is a highly valuable energetic moiety. This work presents a mild method for converting aromatic ketones into novel gem-difluoramino compounds using Me4NSO3NF2. Their structures were confirmed by spectroscopy and crystallography. Compound 2k exhibits high thermal stability, lower sensitivity, and superior detonation performance, demonstrating its potential as a high-energy oxidizer.

We report herein the first copper-mediated three-component modular synthesis of N-fluoroalkyl amides from fluoroalkylcopper species ([CuI & horbar;CF3], [CuI & horbar;CF2CO2Et], and [CuI & horbar;C2F5]), a nitrene precursor (dioxazolone), and an electrophile, featuring broad substrate scope and the unprecedented construction of acyclic N-C2F5 and N-CF2CO2Et structures. The reaction proceeds via reaction of the dioxazolone with the fluoroalkylcopper complex to generate a nitrene/Cu intermediate, followed by nitrene migratory insertion into the [CuI & horbar;CRf] bond as the pivotal step that directly forges the N-fluoroalkyl bond. Such a key step was supported by isolation and single-crystal x-ray characterization of intermediates [(L1)CuIN(CF3)(COAr)] 5c and [CuI(N(CF3)(COAr))2]- 5d. Leveraging the versatile reactivity of copper, these intermediates react with various electrophiles to access a wide range of N-fluoroalkyl-N-alkyl(aryl)amides, and the derivatization of several drug molecules further demonstrates the synthetic utility of this approach.

The intermolecular carbo-halogenation of alkenes provides a direct method for synthesizing alkyl halides. However, existing methods are largely limited to monosubstituted alkenes, and a general catalytic asymmetric intermolecular variant remains an unsolved challenge. Herein, we report a highly regio- and enantioselective intermolecular carbo-halogenation of 1,1-disubstituted alkenes through a nickel/N-heterocyclic carbene (NHC)-catalyzed carbo-magnesiation/electrophilic halogenation strategy. The use of bulky NHC ligands and haloacetonitriles as halogen sources proved crucial for achieving high reactivity and selectivity, facilitating the efficient synthesis of diverse alkyl halides that feature acyclic or cyclic beta-all-carbon quaternary centers. This work significantly advances the field of catalytic asymmetric carbo-halogenation.

Grignard reagents-cornerstones of synthetic chemistry-are hindered by enduring limitations in accessing complex architectures, which poses a persistent synthetic bottleneck. Meanwhile, quaternary carbon (stereo)centres, ubiquitous in bioactive molecules and natural products, remain formidable synthetic targets despite decades of research. Here we introduce a nickel-catalysed carbomagnesiation strategy that simultaneously overcomes these challenges through a rare contra-electronegativity transmetallation (Ni to Mg). This approach enables the efficient and modular synthesis of beta-quaternary Grignard reagents via carbomagnesiation of 1,1-disubstituted alkenes and 1,3-dienes, employing aryl triflate and PhMgBr as carbon and magnesium sources, respectively. The resulting organomagnesium reagents undergo one-pot reactions with diverse electrophiles, delivering stereochemically complex quaternary centres with high precision. Mechanistically, bulky N-heterocyclic carbene (NHC)-based catalysts divert classical cross-coupling pathways, enforcing a counterintuitive Ni-to-Mg transmetallation that defies conventional electronegativity trends while achieving exceptional regio- and enantiocontrol. This contra-electronegativity transmetallation demonstrates substantial potential to advance carbometallation reactions and open new avenues for cross-coupling chemistry.

Cationic rare-earth metal alkyl complexes have proven to be outstanding single-site catalysts, particularly for the coordination polymerization of 1,3-dienes with high catalytic activity and stereoselectivity. Unprecedentedly, the polymerization of the novel bioderived 1,3-diene, namely 2-allylidene-6,6-dimethylbicyclo[3.1.1]heptane (ADH), catalyzed by a cationic scandium alkyl complex, proceeded via a ring-opening cationic mechanism rather than a coordination-insertion pathway. Detailed studies indicated that during the initiation step, the coordination-induced steric repulsion between the catalyst and ADH was critical for generating the active tertiary carbocation, which was formed by the ring-opening of the fused cyclobutane unit in ADH. Density functional theory (DFT) calculations revealed that both coordination polymerization and ring-opening cationic polymerization of ADH can be energetically competitive, and the steric hindrance of the catalyst may play a critical role in determining the polymerization outcome. The resulting poly(ADH) (PADH) exhibited a high glass transition temperature, excellent thermostability, optical transparency, and potential for postmodification.

S-1-Propenyl-L-cysteine (S1PC), a sulfur-containing amino acid naturally present in Allium sativum and first identified in garlic preparations in the 1960s, plays an important role in aged garlic extract (AGE) and a key pharmacological role. Since 2016, it has been found to possess a variety of biological activities, including anti-hypertensive, anti-inflammatory and immunomo- dulatory properties. S1PC has less odour and is less toxic than whole garlic, making it a more attractive option for those looking to reap the health benefits of garlic without the adverse side effects of indigestion and bad breath. S1PC has been found to have blood pressure lowering effects in animal models of hypertension and has immunomodulatory effects both in vivo and in vitro. In addition, S1PC has anti-inflammatory effects, which may help prevent or manage diseases associated with chronic inflammation, such as gingivitis and atherosclerosis. Based on the above findings, S1PC is considered to be another important, pharmacologically active and safe component of AGE, along with its isomer S-allyl-L-cysteine (SAC). In this review, the latest research progress on the physicochemical properties and other aspects of S1PC is summarized, and the possible directions of its application development in the future are also proposed.

In carbohydrate-based drug discovery, fluorine-containing substituents are widely used to enhance pharmacodynamic and pharmacokinetic profiles. However, the precise incorporation of C(sp3)-perfluoroalkyl moieties at the C2 position of sugar scaffolds remains a significant synthetic challenge. In this study, we report a highly efficient and cost-effective protocol for the synthesis of 2-deoxy-2-perfluoroalkyl glycosides from readily available glycals. This protocol demonstrates exceptional substrate generality, encompassing glucal, galactal, rhamnal, sialic acid, and arabinofuranose derivatives. More importantly, this platform enables the efficient synthesis of diverse C-, N-, and O-glycosides (over 50 examples) under gold(I)-catalyzed conditions, including the synthesis of previously inaccessible 2-deoxy-2-CF3-substituted nucleoside analogues. Additionally, photocatalytically generated 2-deoxy-2-CF3 glycosyl anomeric radicals readily undergo Giese-type additions to alkenes, affording alkylated glycosides, or engage in cross-coupling with aryl bromides to deliver antidiabetic drug candidates. Preliminary biological evaluations indicate that 2-deoxy-2-CF3-modified glycosides exhibit enhanced pharmacological properties, underscoring the translational potential of this synthetic technique for advancing carbohydrate-based therapeutics.

In a recent issue of Cell, Wang et al. identify mitoxyperilysis,a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.

Enantioenriched beta-allyl carbonyl compounds constitute an important class of versatile chiral building blocks that can be transformed into a variety of intermediates and utilized in the synthesis of numerous biologically active natural products. Catalytic enantioselective conjugate allyl addition to simple alpha,beta-unsaturated esters provides one of the most efficient approaches for access to such moieties. However, this reaction has not been accomplished for a long time in synthetic chemistry. The natural tendency for 1,2-addition or the formation of stable pi-allyl complexes and reluctance to 1,1-reductive elimination make such a reaction very challenging. Herein, by means of copper(I)-N-heterocyclic carbene (NHC) catalysis, such a problem is successfully addressed, and a broad range of simple alpha,beta-unsaturated esters undergo conjugate allylation with commercially available allylBpin in moderate to high yields with excellent regioselectivity and high enantioselectivity. The hydroxyl group in the NHCs was found to be indispensable for both a high yield and high enantioselectivity. Based on control experiments and DFT calculations, a redox reaction pathway involving reversible oxidative addition of allyl cuprate to simple alpha,beta-unsaturated esters, isomerization of Cu(III) pi-allyl species, and unique 3,3 '-allyl-allyl reductive elimination is proposed rationally. Finally, the synthetic utility of the present methodology is showcased by its application in efficient asymmetric formal syntheses of three bioactive natural products and transformations of the allylation product.

A general method for the direct trifluoromethylation and chlorodifluoromethylation of Reformatsky reagents derived from various amides or ketones using YlideFluor or YlideFluor-CF2Cl was described. This reaction proceeds under mild conditions and exhibits a broad functional group tolerance. The utility of this protocol was demonstrated through the synthesis of trifluoromethylated derivatives of two pharmaceutical agents, donepezil and ibudilast.

Current single-cell metabolomics approaches are limited by insufficient sensitivity, robustness and metabolite coverage. We present an ion mobility-resolved mass cytometry technology that integrates high-throughput single-cell injection with ion mobility-mass spectrometry for multidimensional metabolomic profiling. Ion mobility-enabled selective ion accumulation and cell superposition-based amplification strategies substantially enhance sensitivity, robustness and overall analytical performance. Combined with our computational tool, MetCell, this technology allows high-throughput analysis while achieving exceptional profiling depth, detecting over 5,000 metabolic peaks and annotating approximately 800 metabolites per cell-representing a 3-fold to 10-fold improvement over existing methods. It offers attomole-level sensitivity and captures a broad dynamic range of metabolites within individual cells. Applied to 45,603 primary liver cells from aging mice, it enabled accurate cell-type and cell-subtype annotation and revealed distinct metabolic states and heterogeneity in hepatocytes during aging. This platform sets a new benchmark for high-throughput single-cell metabolomics, advancing our understanding of metabolic heterogeneity at single-cell resolution.

Axon degeneration is a key pathological feature in neural injuries and neurological disorders. MEK1/2 inhibitors (MEKis) are used in cancer therapy but can cause peripheral nerve lesions. Paradoxically, they are being considered for neurodegenerative diseases. Here, we show that MEK inhibition enhances, whereas its activation protects against, injury-or chemotherapy-induced axon degeneration in mouse DRG neurons. Mechanistically, the Raf-MEK-ERK cascade upregulates the critical axon survival factor Nmnat2 via ERK phosphorylation-dependent transcription. The MEKi trametinib decreases Nmnat2 expression and induces axon degeneration in DRG neurons, which is rescued by Nmnat2 overexpression. In contrast, cortical and spinal neurons maintain Nmnat2 transcription via CREB, independent of MEK-ERK, and are resistant to trametinib. Our findings demonstrate a neuron subtype-specific mechanism whereby MEK-ERK promotes axon stability through Nmnat2 upregulation. This context-dependent axon survival paradigm helps explain the vulnerability of PNS neurons to MEKi-induced axon degeneration, highlighting Nmnat2 as a potential target to counteract MEKi-associated neuropathy.

Alkenylboronates represent a cornerstone functional group in modern organic synthesis owing to their versatile reactivity in Suzuki-Miyaura cross-coupling reactions and other key transformations. However, catalytic asymmetric methods for producing stereodefined tetrasubstituted axially chiral alkenylboronates remain underdeveloped. Here, we report a copper-catalyzed atroposelective protoboration of allenes, providing a facile strategy to access tetrasubstituted axially chiral Z-alkenylboronates with excellent regio- and atroposelectivities. The enantiomerically enriched axially chiral alkenylboronates could be further transformed into diverse stereodefined tetrasubstituted axially chiral olefins via the cross-coupling reaction of the C-B bond. This methodology also provides a new avenue to construct C-C or C-N axially chiral alkene-phosphine frameworks.

Developing novel drugs is a long and difficult process, particularly in oncology, where high attrition rates make clinical trials costly and time-consuming. In response, drug repurposing emerges as an efficient alternative: existing compounds can be used effectively in new therapeutic contexts. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase involved in tumor progression, has emerged as a promising target for solid tumor treatment. To identify novel potential DDR1 inhibitors, we applied ESSENCE-Dock, an in-house consensus docking method designed to improve hit enrichment. Using this approach, we performed virtual screening of the DrugBank database, a comprehensive collection of Food and Drug Administration-approved and investigational drugs. To ensure novelty, we performed fingerprint dissimilarity analysis against known DDR1 inhibitors from BindingDB, prioritizing structurally distinct candidates. While several known DDR1 inhibitors ranked among the top-scoring compounds, we prioritized novel, structurally distinct candidates for testing. Biochemical IC50 assays validated three previously unreported DDR1 inhibitors with nanomolar potency, while molecular dynamics simulations confirmed their stable binding within the DDR1 active site. Functional cell-based assays revealed inhibition of DDR1-mediated signaling and cancer cell migration. These findings demonstrate the effectiveness of our consensus-based virtual screening approach in drug repurposing and underscore its potential to streamline oncology drug development.

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that mediate excitatory neurotransmission throughout the brain1. As obligate heterotetramers, their activation requires the binding of both glycine and glutamate2. Although recent structural studies have provided insights into endogenous receptors from select brain regions3, most previous work has relied on recombinant receptors and engineered constructs, which limits our understanding of native NMDARs across the whole brain. Here we identify and resolve ten distinct native NMDAR assemblies from the whole-brain tissue of female C57BL/6 mice using immunoaffinity purification, single-molecule total internal reflection fluorescence microscopy and cryo-electron microscopy. Analyses of the GluN1-GluN2A(S1), GluN1-GluN2A(S2), GluN1-GluN2A(S3), GluN1-GluN2B, GluN1-GluN2A-GluN2B(S1), GluN1-GluN2A-GluN2B(S2), GluN1-GluN2A-GluNX(S1), GluN1-GluN2A-GluNX(S2), GluN1-GluN2B-GluNX and GluN1-GluNX structures reveal that GluN2A is the most prevalent subunit across assemblies. Moreover, the substantial conformational flexibility observed in the GluN2A amino-terminal domain may explain its fast kinetics and dominant role in gating. Dynamic movements of S-ketamine were also captured at the channel vestibule, as was pore dilation in both the GluN1 and GluN2B subunits of a native GluN1-GluN2B receptor. The latter observation represents a previously unknown fully open state of NMDAR. Our large collection of heterogeneous NMDAR structures from whole brain reveals previously unrecognized properties of conformational diversity and channel dilation.

Host-guest binding has been used to develop a universal antagonistic agent for clinically used neuromuscular blocking agents (NMBAs) by preparing ten deuterated acyclic cucurbit[n]urils (ACBs). Train-of-four test with rats reveals that, compared with the nondeuterated counterpart, tetradeuterated compound dACB-4 displays improved activity for reversing the blockade of all clinically used NMBAs, particularly cisatracurium with 43% improvement. Binding constant measurement supports that deuteration provides dACB-4 with increased binding affinity for all NMBAs. The dynamic light scattering experiment shows that, different from the nondeuterated counterpart, which undergoes strong self-aggregation, dACB-4 does not aggregate even at the high concentration of 60 mM. Density functional theory calculation illustrates that deuteration causes the acidity of the CH units to reduce by 1 pKa unit. Thus, the activity improvement of dACB-4 has been tentatively attributed to the contribution of deuteration to weaken intermolecular hydrogen bonds and thus its self-aggregation. In vitro and in vivo studies further confirm that dACB-4 also has improved biocompatibility, with general performance surpassing that of all reported ACBs.