A useful protocol was reported for preparing trifluoromethylated (hetero)arenes from (hetero)aryl boronic acids or their derivatives: using the easily available organocopper(III) complex, (Bu4N+)-Bu-n[Cu(CF3)(4)](-), in the absence of any additives and under an air atmosphere. Preliminary mechanistic studies indicated that the boron substrate acted as a Lewis acid, abstracting one fluoride from the trifluoromethyl group of (Bu4N+)-Bu-n[Cu-III(CF3)(4)](-), thereby initiating an activation process that produced a neutral Cu(III) intermediate, [(L-n)Cu-III(CF3)(3)] (L-n = solvent or none). Rapid transmetallation with the in situ generated [ArB(OH)(2)(F)](-) and subsequent reductive elimination yielded the trifluoromethylated arenes. Detailed examination of the reaction's scope revealed compatibility with a broad range of functional groups, including those with acidic protons and C=C bond. Applications of this protocol for trifluoromethylation onto several drug molecules were demonstrated.

The highly isoselective polymerization of styrenyl monomers is highly desired but faces great challenge, partly because of the limited optional items in the catalyst toolbox. In this study, we synthesized a series of bis(aminophenyl)amido-pincer yttrium and lutetium complexes, and upon activation with a borate, these complexes exhibited high isoselectivity (>99% mmmm) in the polymerization of ortho-methoxystyrene (oMOS) with a notable polar group activation effect. Additionally, these catalytic systems efficiently polymerized oMOS derivatives containing fluoro-and methoxy groups, yielding the corresponding highly isospecific (>99% mmmm) polymers. Density functional theory (DFT) calculations indicated that the C2 symmetry of the ligand skeleton plays a critical role in the lutetium-catalyzed highly isoselective polymerization of oMOS. The resultant polymers can serve as effective building blocks for the synthesis of isotactic polystyrene derivatives.

(3-Phellandrene ((3-Phe) is a naturally occurring compound featuring a cyclic conjugated diene structure with an exo-methylene group, making it a promising biomass-derived monomer for polymerization. However, its concentration and purification are challenging. In this study, we report an efficient synthetic strategy for the preparation of (3-Phe with high yield and purity. In the catalysis of cationic half-sandwich rare-earth metal alkyl species, the polymerization of (3-Phe was successfully achieved via a possible cationic mechanism.

Natural products and their derivatives have long served as a prolific reservoir for drug discovery. All-trans retinoic acid (ATRA) regulates lipid metabolism and shows anti-atherosclerotic potential, but its application is limited by poor drug-like properties and retinoid-related toxicity. Here, an allene-based Chem-Stamp technology has empowered the efficient construction of a diverse non-natural ATRA library by fine-tuning the number of isoprene units, the side chain, and the terminal group, leading to the identification of G301-WSS-2003 as a novel ATRA-based LDLR up-regulator. In vivo, G301-WSS-2003, with favorable exposure and bioavailability (e.g., t 1/2 > 5 h, F > 30%), reduced serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) by 27%, 36%, and 26%, respectively, and significantly attenuated atherosclerotic lesion formation with no liver function abnormalities. These results highlight that Chem-Stamp is a powerful technology platform in the discovery, which results in identifying G301-WSS-2003 for further development as a promising candidate for the treatment of atherosclerosis.

The microphthalmia/transcription factor E (MiT/TFE) and upstream stimulating factors (USFs) subfamilies be-long to the basic Helix-Loop-Helix Leucine zipper (bHLH-LZ) transcription factor superfamily, serving as key hubs regulating cellular physiological homeostasis and disease progression. The MiT/TFE family comprises four members, namely MITF, TFE3, TFEB, and TFEC, with a signature structural feature of three amino acid insertions in the Leucine zipper (LZ) domain, enabling the formation of dynamic dimers. This family regulates cellular metabolic stress and tissue-specific functions through the autophagy-lysosome pathway. The USFs family includes two members, USF1 and USF2, which rely on stable tetrameric conformations mediated by the LZ-Ext module to enhance transcriptional efficiency via DNA looping, thereby participating in basic transcriptional regulation and maintenance of multi-system homeostasis. Dysfunction of both families is closely associated with cancer, metabolic diseases, immune disorders, and other conditions, and their unique structural domains provide important targets for targeted therapy. This review systematically summarizes the discovery history, member characteristics, structure-function relationships, and pathological significance of the MiT/TFE and USFs families, focuses on the development strategies and progress of small-molecule inhibitors, and finally prospects the future research directions and clinical transformation potential of this field, aiming to provide a theoretical basis and innovative ideas for the precision medicine practice of related diseases.

Radical fluoroalkylation via electron donor-acceptor (EDA) complex photochemistry stands out as a particularly attractive approach, owing to its mild conditions and the absence of an external metal photocatalyst or organic dye. Fluoroalkyl sulfones, valued for their stability, accessibility, and structural tunability, have emerged as versatile precursors for radical fluoroalkylation. Herein, we present a photocatalyst-free and straightforward method for direct fluoroalkylation through an EDA complex, utilizing inexpensive iodide anion as an electron donor and fluoroalkyl sulfones as acceptors. Upon visible light irradiation, the EDA complex undergoes single-electron transfer (SET) to generate fluoroalkyl radicals, which subsequently react with a diverse array of silyl enol ethers with high efficiency. The method features mild reaction conditions, broad functional group compatibility, and an extensive substrate scope that encompasses bioactive molecules and sterically demanding architectures. Mechanistic investigations indicate the involvement of an iodide-mediated EDA complex and support the proposed radical-generation pathway. This work establishes a practical and sustainable platform for fluoroalkylation, underscoring the utility of iodide in EDA-based photochemistry and broadening the scope of radical synthetic methods.

A unified total synthesis of 16 stereochemically defined 5,6-diol-bearing tetrangomycin-type angucyclines, including PD-116740, TAN-1085, himalaquinone G, and their congeners, was achieved. The synthesis features an acid-catalyzed hydration and subsequent retro-Friedel-Crafts-type ring-opening of a strained cyclobutene precursor to rapidly elaborate the angucycline framework. A completely catalyst-controlled reduction via Noyori asymmetric transfer hydrogenation (ATH) was then implemented to elaborate the C5/C6 diol stereocenters, which overrides inherent substrate biases, precisely transforming a racemic alpha-hydroxy ketone into all four possible C5/C6 diol stereoisomers. Access to this complete stereoisomeric matrix enabled the stereochemical reassignment of himalaquinone G from the originally assigned cis-(5R,6S)-diol to trans-(5R,6R)-diol. Antitumor activity profiling identified the unnatural enantiomer of PD-116740 as a highly potent agent (IC50 = 0.24 & micro;M against A375 melanoma cells), outperforming its natural counterparts.

The reversible sigma-dimerization of radicals is a fundamental process in bond formation and cleavage, yet achieving this with an isolable heavy carbyne analogue has remained a paramount challenge. Herein, we report the synthesis and characterization of an isolable germylyne radical that demonstrates remarkable ambient stability while undergoing clean, reversible sigma-dimerization via a Ge-Ge single bond. This reversible process, which exhibits a pronounced thermochromic response, is thoroughly elucidated through variable-temperature NMR/EPR spectroscopy and X-ray crystallography, revealing a moderate bond dissociation enthalpy. Beyond dimerization, this germylyne radical acts as a versatile synthon for main-group bond activation, readily cleaving chalcogen-chalcogen (S-S, Se-Se), phosphorus-phosphorus (in P-4), and even challenging aromatic carbon-chlorine (C-Cl) bonds. This work provides the direct structural evidence of a heavy carbyne's dimerization pathway and establishes a new platform for dynamic covalent bonding in main-group chemistry, with implications for stimuli-responsive materials and radical-mediated activation.

A synergistic photoredox/cobalt-catalyzed protocol for the construction of 6-10-membered allylic alcohols through enantioselective intramolecular alkenylation of aldehydes is presented. Such processes enabled access to a variety of medium-sized rings bearing exocyclic double bonds and application in the simultaneous establishment of central and axial stereogenicity, representing a general platform for the synthesis of enantioenriched cyclic allyl alcohols with diverse ring sizes. Mechanistic studies and DFT calculations elucidated the involvement of an alkenyl radical intermediate and models of stereochemical induction.

STING, a central component of the cGAS-STING innate immune signaling pathway, is implicated in various autoimmune and inflammatory disorders when aberrantly activated. In this study, an L-configured homoproline derivative Z55 was obtained through structural optimization of the natural product resibufogenin (RBG), which exhibited approximately threefold greater cellular inhibitory activity against STING than RBG (IC50 = 0.40 +/- 0.04 mu M for Z55 vs. 1.42 +/- 0.11 mu M for RBG), and maintained favorable in vitro safety. Surface plasmon resonance (SPR) analysis confirmed high-affinity binding of Z55 to hSTING (KD = 2.31 mu M), and a cellular thermal shift assay (CETSA) further demonstrated that Z55 directly engages endogenous STING in living cells, with a thermal stabilization of 4.31 +/- 0.7 degrees C. Mechanistic studies, including DTT stability and SPR reversibility assays, support a non covalent interaction mode, while molecular docking provided structural insight into the binding interface. Mechanistically, Z55 inhibited STING phosphorylation and downstream activation of p-TBK1 and p-IRF3, leading to decreased levels of key inflammatory cytokines (IL-1 beta, IL-6, and TNF alpha) in both colon tissue and serum of mice with ulcerative colitis. Importantly, this series of compounds exhibited marked chiral-toxicity separation, with the L-configuration identified as the optimal pharmacophore for both efficacy and safety. Collectively, these findings highlight Z55 as a promising STING-targeting lead candidate for the treatment of inflammatory diseases.

Detection of alpha-synuclein (alpha-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, alpha-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.

Rationale Comprehensive characterization of lignin-derived oligomers remains a major analytical challenge because of their high structural diversity and the lack of methods capable of resolving native interunit linkages in complex biomass-derived mixtures. Molecular-level understanding of these oligomers is essential for elucidating lignin depolymerization mechanisms and guiding biomass valorization strategies.Methods Lignin oligomers generated from methanol-based flow-through solvolysis of birch sawdust were analyzed by high-performance liquid chromatography coupled with ultraviolet detection and tandem mass spectrometry (HPLC-UVD/MSn). Chromatographic separation was performed on tandem reversed-phase C18 columns, and structural characterization was achieved using electrospray ionization Orbitrap mass spectrometry with higher-energy collisional dissociation (HCD).Results Distinct chromatographic behaviors were observed for lignin-derived products with different degrees of polymerization, enabling differentiation of monomeric and oligomeric species. Tandem MS analysis of representative oligomers revealed characteristic fragmentation pathways that enabled structural elucidation of oligomers. beta-O-4 linkages were identified as the predominant interunit structures, and native beta-beta motifs were also characterized.Conclusions Untargeted molecular-level characterization of lignin-derived products generated from methanol-based flow-through solvolysis of birch biomass provides direct insights into the composition and interunit linkages of native-like lignin oligomers. These findings reveal the structural diversity of biomass-derived oligomers and bridge the gap between model-compound studies and real biomass-derived lignin systems.

Inwardly rectifying potassium (Kir) channels play key roles in regulating membrane potential and potassium transport through voltage-dependent inhibition by cytoplasmic Mg & sup2;(+) and polyamines. Despite decades of extensive studies, the structural basis for polyamine-mediated inward rectification remains unclear. Here, we present cryo-EM structures of the heteromeric Kir4.1/5.1 channel-which is critical for brain and kidney function and whose dysfunction causes EAST/SeSAME syndrome-in its apo state and in complex with spermine, a channel blocker named VU0134992, and EHop-016, an inhibitor identified in this study. The structures of Kir4.1/5.1, in an opposite 2:2 heterotetrameric assembly, suggest an inner-ring blockage mechanism, where polyamines and channel blockers with different stoichiometries bind in a membrane-parallel orientation at the upper site of the transmembrane central cavity. Together with electrophysiology and molecular dynamics simulations, our findings provide mechanistic insights into inward rectification, channel inhibition, and the pharmacology of Kir channels.