C-H functionalization has emerged as a powerful strategy in modern organic synthesis, enabling direct transformations of simple hydrocarbons into structurally diverse and value-added molecules. Among various approaches, diaryliodonium salts represent versatile intermediates that can be directly prepared from arenes and subsequently coupled with a wide range of nucleophiles, providing an efficient platform for rapid molecular diversification. However, one-step C-H functionalization to access diaryliodonium salts often suffers from narrow substrate scope, while the ensuing coupling reactions are hampered by limitations in aryl transfer selectivity. These challenges have constrained the broader application of this methodology. Recent advances in the design of 3,5-dimethylisoxazol-4-yl (DMIX)-substituted hypervalent iodine reagents have simultaneously overcome both substrate and selectivity limitations, offering new opportunities for expanding the utility of diaryliodonium salts in C-H functionalization. This review highlights the discovery and properties of DMIXbased reagents, and surveys their latest applications in achieving structurally diverse C-H functionalization, highlighting their potential to advance the field of hypervalent iodine chemistry.

The fluorinated functional groups represent privileged and irreplaceable motifs in pharmaceuticals and agrochemicals. However, certain fluorinated group-containing compounds, including trifluoromethyl group have recently been classified as per- and polyfluoroalkyl substances (PFAS) due to their high stability, environmental mobility and toxicity. Fortunately, halodifluoromethyl groups (-CF2X, X = Cl, Br, I) can be degraded into nonpersistent compounds and serve as the halogen bond donors, which are distinctive among fluorinated substituents. Despite the importance of these groups, a general method for the installment of halodifluoromethyl groups into aromatics remains underexplored. Here we report a facile and efficient synthesis of chloro(bromo, iodo)difluoromethylarenes through nickel-mediated halodifluoromethylation of (hetero)aryl chlorides(bromides) with TMSCF2Cl or TMSCF2Br. The distinct reaction mechanism involves the insertion of difluorocarbene into the in situ generated aryl nickel(II) halide complex (Ar-Ni(II)-X), followed by oxidant-induced reductive elimination from the resulting aryldifluoromethyl nickel(II) intermediate (ArCF2-Ni(II)-X).

Herein, we report a highly efficient synthesis of aliphatic nitro compounds bearing multi-contiguous stereocenters in good yields (up to 72%) with excellent diastereo- and enantio-selectivities (up to 12:1 dr, and >99% ee) by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to nitroalkenes with iridium-catalyzed asymmetric allylic substitution reaction. Stereodivergent construction of nonadjacent stereocenters (1,3-positions) has been achieved by combining two chiral catalysts with different enantiomers. By first introducing a chiral center at the beta-position of the nitro group, highly diastereoselective control has been achieved in iridium-catalyzed allylic substitution reaction of prochiral nitro compounds.

Aim Dorzagliatin is a glucokinase (GK) activator, restoring glucose homeostasis in type 2 diabetes. We investigated the effects of dorzagliatin on cognitive traits using Mendelian randomization (MR), with validation in a spontaneous diabetic rat model.Methods A two-sample MR study was conducted to investigate the causal effects of GK activation on neurodegenerative traits. Utilizing genome-wide association study summary statistics, we selected independent genetic variants of GCK (encodes GK) associated with lower HbA1c as instrumental variables to mimic GK activation. An animal validation study was further performed. Goto Kakizaki rats and Wistar rats were treated with vehicle or low-dose dorzagliatin (8mg/kg, i.g, bid, below the therapeutic level) for 36 weeks. Morris water maze (MWM) test, western blot analyses were carried out to investigate the neuroprotective effects of dorzagliatin and explore the potential mechanisms.Results Genetically mimicked GK activation causally decreased risk of memory loss (OR 0.21 per 1% lower HbA1c, 95% CI 0.05-0.91) and was associated with higher scores of prospective memory task, symbol digit substitution task and intelligence. MR results also implied that GK activation had cognitive protective effects not solely attributed to glucose-lowering. Low-dose dorzagliatin treatment in young Goto Kakizaki rats prevented spatial memory impairment occurred in adulthood in the MWM test. It also significantly prevented the reduced expression of insulin receptors, glucose transporters, and synaptic proteins in the brains of Goto Kakizaki rats.Conclusions Dorzagliatin protects against cognitive impairment under diabetes conditions. Maintaining glucose homeostasis directly regulates insulin pathway and glucose uptake, as well as enhances neurotransmission processes in the hippocampus. These findings not only highlight dorzagliatin as a promising therapeutic option for preventing diabetes-associated cognitive decline but also provide critical mechanistic insights into the role of GK modulated glucose homeostasis in preserving brain function, offering a potential translational strategy for clinical intervention.

Two novel difluoroaminofurazan compounds were synthesized through four steps from methyl 4-aminofurazan-3-carboxylate, involving ester exchange, condensation, cyclization, and fluorination. These compounds, incorporating the key difluoroamino (NF2) explosophore to enhance enthalpy of formation, exhibit promising energetic properties. Thermal analysis (TGA/DSC) revealed that the mono-1,3,4-oxadiazole-bridged derivative melts at 66.02 degrees C and begins decomposition at 149.23 degrees C. It possesses a density of 1.881 gcm- 3, an enthalpy of formation of 411.1 kJmol- 1, a detonation velocity of 7505 ms- 1, and a detonation pressure of 24.9 GPa. In comparison, the bis-1,3,4-oxadiazole-bridged analog demonstrates superior thermal stability, with a melting point of 182.44 degrees C and an onset decomposition temperature of 220.09 degrees C. Its properties include a density of 1.743 gcm- 3, an enthalpy of formation of 447.8 kJmol- 1, a detonation velocity of 7573 ms- 1, and a detonation pressure of 25.0 GPa.

Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating immunosuppression was poorly depicted. To address this, serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17 beta-chloroformate (17 beta-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from the GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Through analysis of patient serum and murine transplantation models, we identified D-Kyn as a key metabolite whose elevated levels correlate with stable graft function. We found that D-Kyn, more effectively than its chiral counterpart L-Kyn, inhibits the inflammatory activity of M1 macrophages. This suppression is mediated via the PHGDH/TLR4/Caspase-1 pathway, reducing the transcription and secretion of inflammatory cytokines. In murine models of skin and kidney transplantation, D-Kyn treatment demonstrated potent immunosuppressive effects, attenuating macrophage-mediated inflammation and CD8 + T cell activation, potentially through regulation of macrophage-derived IL-23a. Our findings reveal D-Kyn as a promising therapeutic candidate for preventing acute rejection and improving transplant outcomes and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.

De novo formation of the aromatic ring is an attractive strategy for atroposelective synthesis, but its application to planar-chiral macrocycles remains challenging. Herein, we report a rhodium-catalyzed enantioselective synthesis of planar-chiral macrocycles via de novo isoquinoline construction. This method is characterized by high levels of enantioselectivity (up to 96% ee), regioselectivity (up to >20:1 rr), and functional group tolerance, providing a series of isoquinoline-based macrocyclic atropisomers. Furthermore, the synthetic utility of this protocol is validated via a mmol-scale reaction and post-modification process of the product. Mechanistic studies, including deuterium labeling, kinetic isotope effect, and DFT calculations, support C & horbar;H bond cleavage as the rate-determining step and elucidate the origin of the stereoselectivity.

Background: Chiral pesticides are increasingly important in agrochemicals, with enantiomers differing significantly in bioactivity, toxicity, and environmental impact. Rapid and robust methods for resolving these enantiomers in complex matrices are essential for regulatory monitoring and mechanistic studies. Results: We developed a separation-free 19F NMR chemosensing platform using dual-stereocenter 19F-labeled Pd probes. The method enables direct enantiodifferentiation of N-heterocyclic pesticides, including complex cases like difenoconazole where all four stereoisomers are fully resolved in a single 19F spectrum. Quantitative enantiomeric excess (ee values) determination shows excellent linearity, with deviations from the true ee values of less than 2 %. The platform also resolves six pesticides simultaneously in a mixture and, in soil extracts, monitors in situ stereoselective degradation, revealing significant degradation bias between enantiomers. Significance: Dual-stereocenter 19F NMR probes deliver a practical alternative to chiral chromatography for pesticide residue analysis, combining operational simplicity, matrix tolerance, multicomponent capability, and quantitative rigor. The method enables direct, separation-free readout of stereochemistry and kinetics in complex samples and reveals in situ enantioselective degradation pathways. These attributes provide actionable insight for precision application, environmental risk assessment, and regulatory surveillance of chiral agrochemicals.

The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven new derivatives (6-13) were synthesized based on an efficient biomimetic synthesis of sarocladione. Evaluation of their antiproliferative activities against human cancer cell lines demonstrated that the intact macrocyclic scaffold is indispensable for activity. Extension of the conjugated pi-system led to the identification of compound 8, which exhibited approximately four-fold enhanced potency against HCT116 cells (IC50 = 1.86 mu M) compared with the parent natural product. Stereochemical analysis further revealed the critical role of the (5R)-configuration at C-5. Phenotypic investigations indicated that compound 8 induces concentration-dependent G2/M phase cell cycle arrest, followed by apoptosis, suggesting a cell cycle-dependent antiproliferative effect. Overall, this study highlights sarocladione as a promising marine-derived scaffold for further antiproliferative optimization.

A photoredox-catalyzed system has been developed for the deoxyphosphonylation and deoxyphosphinylation of alkyl alcohols via thianthrenium salts. This methodology features simple reaction conditions, avoids the use of expensive reagents, and enables efficient recovery and reuse of thianthrenium reagent as hydroxyl-activating agent. Notably, both transformations exhibit broad substrate scope and good functional group compatibility, and have been successfully applied to the late-stage modification of various complex bioactive molecules. This protocol represents a promising methodology for practical synthesis of alkylphosphonates and alkylphosphinates.

In this paper, a novel synthetic route is presented for the production of 99.99% high-purity anhydrous rare earth fluoride. First, organic system was used to produce high-purity diphenylpropanedione salt with hydrated rare earth salt as raw material through complex reaction, followed by recrystallization, and high-temperature vacuum drying to remove water of crystallization. Then, the resulting complex salt was reacted with ammonium hydride fluoride to prepare high-purity anhydrous rare earth fluoride. This method avoids the challenges associated with traditional dry methods, such as harsh reaction conditions and the easy introduction of impurities, as well as the high oxygen content and filtration difficulties of wet methods. The purity, oxygen content, and composition of the prepared rare earth fluoride products were analyzed using thermal analyzers, scanning electron microscopy, X-ray diffraction, inductively coupled plasma mass spectrometry, and an oxygen analyzer. The results demonstrated that this method produces rare earth fluoride with high purity, anhydrous properties, low oxygen content, and excellent crystallinity. This approach represents a green, efficient, and innovative preparation method for rare earth fluoride and offers a new pathway for the production of high-purity rare earth fluoride compounds.

Parkinson's disease (PD) pathogenesis is driven by alpha-synuclein (alpha-syn) amyloid aggregation, with the flexible C-terminal region mediating pathological interactions with cellular receptors and facilitating disease propagation and neuroinflammation. Through immunization with human alpha-syn fibrils and iterative neuronal binding and propagation assays, we identify H21 as a high-affinity fibril-specific monoclonal antibody. H21 selectively binds to alpha-syn fibrils and specifically targets the C-terminal region. H21 competitively blocks interactions between alpha-syn fibrils and established receptors and binding partners, including FAM171A2, RAGE, LAG3, and LC3B. Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) studies reveal that H21 engages alpha-syn fibrils in a periodic manner, inducing conformational remodeling in the fibril architecture. In a PD mouse model, H21 treatment reduces pathological alpha-syn spreading, suppresses neuroinflammation, and significantly improves motor outcomes. These findings underscore the rational design and therapeutic potential of fibril-specific antibodies targeting the C-terminal region of alpha-syn to halt PD progression.