A versatile synthetic strategy has been developed for the construction of a series of peripherally BN‑embedded fluoranthenes. The key step involves a tandem deprotonation/cyclization sequence from readily accessible imine precursors, affording the desired BN‑fluoranthene cores in good yields. Site‑selective bromination at the C‑5 position, which is remote from the BN‑embedded ring, was achieved and exploited for subsequent Suzuki and Sonogashira cross‑coupling reactions to install various aryl and alkynyl substituents. Structural analyses, including X‑ray crystallography and theoretical calculations, confirm a highly planar architecture with delocalized frontier molecular orbitals and show that replacing a C═C unit with a B-N bond markedly alters the local aromaticity of the five‑membered ring. When examined for their optical behavior, most of the synthesized derivatives exhibited intense fluorescence in dichloromethane, with quantum yields as high as 84%. Notably, while alkyl and aryl substituents caused little change in the spectral profiles, the incorporation of conjugated alkynyl groups led to consistent bathochromic shifts in both absorption and emission.

We report a visible-light-driven, metal-free iodination of arenes using aryldibenzothiophenium (Ar-DBT) salts and potassium iodide. This transformation operates efficiently under air with KI as the optimized iodide source, forming an electron donor-acceptor (EDA) complex that generates aryl radicals upon visible-light irradiation. This protocol exhibits broad functional group tolerance across electronically diverse arenes, heterocycles, and sterically congested substrates. Notably, the synthetic utility of this protocol is demonstrated through the late-stage diversification of a wide array of structurally complex bioactive, agrochemical molecules, and functional molecules, as well as the efficient synthesis of dihalogenated xantphos derivatives.

This study reports an optimized method for the synthesis of spiro-1,2-dihydropyridines via the cycloisomerization of 3-aza-1,5-enynes, catalyzed by heterogeneous gold(I)-polyoxometalate (POM) hybrids. By replacing traditional homogeneous catalysts with these hybrid systems, we achieved high yields (up to 82% isolated) in short reaction times, while minimizing product degradation. The reaction scope was demonstrated across a broad range of substrates, including aryl, alkyl, and heterocyclic derivatives, as well as variations in ring size and nitrogen substituents using 5 mol % of [AuI(IPr)(MeCN)][H5P2W18O64] as catalyst.

Gut microbiota dysbiosis is significantly associated with the onset and progression of cough variant asthma (CVA). Targeting and improving gut microbiota dysbiosis may serve as a promising strategy for CVA. Suhuang antitussive capsule (SH) is the sole clinically approved traditional Chinese patent medicine specifically indicated for managing CVA. Herein, we initially identified arctigenin (AG) as one of the effective components detected and preliminarily screened from SH for its potential in treating CVA. AG significantly ameliorates ovalbumin (OVA)-induced CVA symptoms, alleviates gut dysbiosis, and improves intestinal barrier function. Specifically, AG alleviates CVA symptoms in a gut microbiota-dependent manner, as demonstrated by antibiotic treatment and fecal microbiota transplantation (FMT). 16S rDNA sequencing revealed that AG treatment could notably enrich the commensal bacterium Bifidobacterium pseudolongum (B. pseudolongum), which is typically reduced in CVA. The mono-colonization with B. pseudolongum also showed a reduction in CVA severity. Gas chromatography-mass spectrometry (GC-MS) metabolomic analysis identified acetate as the key and main serum metabolite induced by B. pseudolongum. We demonstrated that acetate enters pulmonary circulation and activates the aryl hydrocarbon receptor (AHR). Validation using AHR antagonists, siRNA knockdown, chromatin immunoprecipitation (ChIP) assays, luciferase reporter experiments, and molecular docking confirmed that acetate-mediated AHR activation suppresses interleukin-33 (IL-33) secretion from lung epithelial cells, thereby preventing CVA progression. These findings suggest AG, one of the effective components in SH, exhibits prebiotic-like effects to alleviate CVA and highlight the potential of targeting specific gut microbiota species for CVA treatment.

In the presence of AgSbF6, the Cp*Co(CO)I2-catalyzed reaction of 3-methyl-1-(pyrimidin-2-yl)-1H-indoles with benzofuran-derived azadienes, 2-arylidene-N-mesylbenzofuran-3(2H)-imines, affords 2-(benzofuran-2-yl)(aryl)methyl-substituted indoles. The reaction between 1-(pyrimidin-2-yl)-1H-indoles and α,β-unsaturated imines, N-tosyl-1,3-diarylprop-2-en-1-imines, under the same conditions yields 2-aminoallylated indoles.

A practical photoredox-driven protocol is described for the multicomponent synthesis of sulfonylated indole-fused medium-sized N-heterocycles using readily accessible, modular thianthrenium salts together with N-indolyl phenylacrylamides and DABCO·(SO2)2. Thianthrenium salts serve as general precursors of alkyl and aryl radicals, enabling the efficient and diverse generation of alkyl or aryl sulfonyl radicals via in situ capture of sulfur dioxide while avoiding the use of highly toxic sulfonyl chlorides or sulfonyl hydrazines as sulfonyl sources. Meanwhile, a gram-scale experiment afforded the sulfonylated indole-fused 1,4-diazepinone in good yield and recovered thianthrene in high yield, demonstrating high atom and step economy via the formation of multiple C-S and C-C bonds in a single orchestrated operation.

Heterocyclic aromatic amines (HAAs) are procarcinogens formed during the cooking of meat and fish and could potentially contribute to hepatocellular carcinoma. Although several HAAs are classified as possible or probable human carcinogens, most mechanistic studies have relied on rodent models, despite well-documented interspecies differences in HAA bioactivation by cytochrome P450 (CYP) isoforms. In this study, we investigated the regulation of CYP1A by the HAA 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) using complementary primary human hepatocytes and Hepoid® with HepaRG cells, a long-term 3D liver spheroid model. IQ at concentrations ranging from 0.1 to 20 µM strongly induced CYP1A1 and CYP1A2 expression and enzymatic activity following acute and chronic exposure, whereas other major hepatic CYP isoforms remained unaffected. This response was specific to IQ among other HAAs tested and to human hepatocytes and persisted for up to 28 days in 3D spheroids. IQ-induced CYP1A expression required transcriptional activation and involved the aryl hydrocarbon receptor (AhR). Using complementary pharmacological and genetic approaches, luciferase reporter assays and ligand-binding assays, we demonstrate that IQ is a direct AhR ligand that activates the canonical AhR-xenobiotic response element (XRE) signaling pathway in human hepatocytes. These findings indicate that IQ is a potent and selective inducer of CYP1A through the AhR and induces a sustained human-specific response upon repeated treatment. Persistent CYP1A induction and AhR activation may enhance the bioactivation of IQ and other co-occurring CYP1A substrates, highlighting the value of long-term human-relevant models to improve risk assessment of chemical carcinogens.

Sulfonyl exchange electrophiles are increasingly used in covalent probe and drug discovery, yet their intrinsic reactivity and plasma stability remain poorly defined, limiting rational warhead selection. Here we establish a systematic LC-MS framework to quantify the reactivity of sulfonyl imidazole and triazole electrophiles across key biological nucleophiles together with matched plasma stability. Sulfonyl imidazoles display attenuated cysteine reactivity and markedly improved stability while retaining intrinsic tyrosine reactivity, whereas sulfonyl triazoles exhibit high electrophilicity and rapid degradation. These data reveal clear relationships between aryl electronics, leaving group ability, nucleophile selectivity, and in vivo-relevant stability. To demonstrate practical utility, we applied a SuFEx-click transformation to convert the kinase-directed probe XO44 into a sulfonyl imidazole analogue, yielding a stable SuDEx probe (JL-51) that maintains the proteome-labeling profile of the parent reagent. The corresponding sulfonyl triazole congener was rapidly hydrolyzed. This work provides a mechanistic foundation and practical strategy for designing next-generation sulfonyl exchange covalent probes.

Zhi et al. reported compound 36 as a potent reversible inhibitor of human recombinant monoacylglycerol lipase (hrMAGL; IC50 = 15 nM) with excellent selectivity over other targets. To develop potential PET tracers for imaging MAGL, we synthesized compound 36 as a reference compound. Surprisingly, we observed a significant discrepancy between the reported potency and our findings in two well-established in vitro assays. Compound 36 exhibited no inhibition of endocannabinoid hydrolysis in HEK293 lysates overexpressing human MAGL in a glycerol-based assay at 1 μM. In the competitive ABPP assay, it appeared completely inactive inhibiting MAGL in mouse whole-brain proteome even at 100 μM. In addition, eight structural analogs (2-9) of compound 36 also failed to show any significant MAGL inhibition. Interestingly, when the synthetic substrate 4-nitrophenyl acetate, also used by Zhi et al., was employed, compound 36 inhibited MAGL more effectively than in glycerol-based assay, with an IC50 value of 143 nM, being almost 10-fold less potent than reported. In our reversibility assay, compound 36 exhibited measurable MAGL inhibition only at a concentration of 100 μM. In summary, this study contradicts the earlier report and therefore, compound 36 should be used with caution as a research tool in studies exploring MAGL inhibition.

Small molecules that simultaneously suppress nitric oxide (NO) and interleukin‑6 (IL‑6) offer a strategy to alleviate pathological inflammation. Building on our previous work with aryl‑substituted azaheterocycles, we synthesized 33 new pyrimidine and azolopyrimidine derivatives bearing amino, amide, hydroxyl, or halide groups to enhance hydrogen‑bonding capacity and improve inhibitory activity against both mediators. Screening in C57BL/6J mouse peritoneal macrophages identified nine compounds that markedly inhibited NO production at 50 µM. Two leads-triazolo[1,5‑a]pyrimidine 12bc and dihydropyrimidine carboxamide 7a-emerged as potent dual inhibitors. Compound 7a showed IC50 values of 0.47 µM (NO) and 0.1 µM (IL‑6); 12bc gave 8.66 µM (NO) and 0.85 µM (IL‑6), both with acceptable cytotoxicity. In human PBMC‑derived monocytes, both compounds dose‑dependently suppressed LPS‑induced IL‑6 secretion; 12bc was slightly more potent, reducing IL‑6 to near‑baseline at 100 µM, comparable to dexamethasone. In an LPS/ATP pyroptosis model, they protected monocytes from inflammatory death, with 12bc nearly restoring normal cell morphology. Docking studies into mouse iNOS and IL‑6 suggested plausible binding modes and structure-activity relationships. These (azolo)pyrimidine scaffolds represent promising leads for safe, dual‑acting anti‑inflammatory agents.

The use of ester-derived electrophiles in transition-metal-free electroreductive C(sp[3])─C(sp[3]) bond formation remains largely unexplored. Herein, we report a sacrificial-anode-enabled electroreductive cross-coupling of simple unsaturated carboxylates with unactivated alkyl halides. Aryl, alkenyl, and alkynyl carboxylates are readily incorporated, affording methylene-bridged alkylarenes together with allylic and propargylic C(sp[3])-rich frameworks under mild conditions. Mechanistic studies support independent single-electron reduction of both electrophilic partners, followed by radical-radical coupling, alkoxide elimination, and cathodic deoxygenation via a Clemmensen-like reduction pathway. This work establishes unsaturated carboxylates as a new class of alkylating reagents for electroreductive C(sp[3])─C(sp[3]) bond formation.

Gut microbiota modulates gut-brain crosstalk in Parkinson's disease (PD), yet effective therapies are still lacking. Herein, we report an orally administrable microalgae-nanozyme platform (SP@SKCN) via combining sulfur/potassium (S/K) co-doped carbon nitride (SKCN) with Spirulina platensis (SP), offering a novel therapeutic strategy for PD. Uniform S-K co-doping significantly narrows the bandgap of carbon nitride (2.2 eV), endowing SKCN with high near-infrared (NIR)-photocatalytic activity and a star-shaped network morphology, realizing NIR-driven water splitting for H2/O2 generation. Meanwhile, SKCN exhibits superoxide dismutase (SOD)/catalase (CAT) mimetic enzyme activities, efficiently scavenging reactive oxygen species (ROS) and synergistically alleviating inflammation. SP incorporation protects SP@SKCN from gastric acid degradation, prolongs its intestinal retention time, and mediates sustained SKCN release. Notably, SP@SKCN remarkedly improves motor deficits, gastrointestinal dysfunctions, and dopaminergic neuron loss in PD mice. 16 S rRNA sequencing and targeted metabolomics reveal that SP@SKCN treatment reverses both PD-associated microbiota changes and the MPTP-induced reduction in indole-3-lactic acid (ILA). Further experiments indicate that SP@SKCN alleviate intestinal inflammation and gut barrier disruption, consequently attenuating systemic inflammation. Mechanistically, SP@SKCN restore the ILA/aryl hydrocarbon receptor (AHR)/NF-κB signaling caused by disturbed gut microbiota mediated the glial cells activation, which eventually reduce dopaminergic neuron death. Collectively, SP@SKCN ameliorates PD via regulating the microbiota-ILA-brain axis.

Damage or loss of hair cells, the sensory cells for hearing, is caused by ototoxic drugs or acoustic trauma, and results in permanent hearing loss because the adult cochlea lacks regenerative capacity. Therefore, identifying pathways that regulate hair cell survival is critical. Here we investigate a novel pathway, aryl hydrocarbon receptor (AhR) signaling in the cochlea. We demonstrate for the first time, the expression pattern of AhR in the cochlea under physiological conditions and after exposure to neomycin or noise. Under physiological conditions, AhR was strongly expressed in glia surrounding spiral ganglion neurons with low expression in the organ of Corti. Following neomycin treatment or noise exposure, AhR expression increased in supporting cells suggesting a dynamic response to hair cell injury. This hair cell to supporting cell communication is mediated in part by purinergic signaling, since treatment with ATP mimicked the effect of neomycin, and treatment with the purinergic antagonist suramin eliminated AhR upregulation. In addition, deletion of AhR from the organ of Corti significantly increased hair cell loss after neomycin treatment compared to controls with normal AhR levels. Our findings establish AhR as a cellular biosensor in supporting cells which is upregulated during hair cell injury to regulate the survival of hair cells.

A redox-active bifunctional Ru(II)-catalyzed meta-(aryl)C-H tert-alkylation strategy involving bio-relevant 3-arylquinoxalin-2(1H)-one/2-arylquinoxaline scaffolds with tertiary α-bromo-carbonyls has been devised. The structural/electronic characteristics of tert-alkyl bromide in combination with a SET radical pathway and σ-activation mechanism enable exclusive site selectivity at the remote meta-(aryl)C-H bond and nullify native directing-group-controlled, easily accessible ortho-(aryl)C-H/peri-C-H tert-alkylation.