Mechanistic studies of the transmetalation of the trifluoromethyl group from an ionic Cu(I) complex Q+[Cu(CF3)2]- to a well-defined chlorinated Cu(III) complex trans-[Cu(CF3)2(Cl)(CH2CN)]-Q+was reported. The combined experimental and computational results including kinetics of the process, reactions in the presence of excess chloride salt, or radical scavengers such as TEMPO or 1,1-diphenylethene (DPE), 1,4-dinitrobenzene (DNB), strongly support a concerted metathesis pathway. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Propofol, a common anesthetic, has unclear effects on fetal brain development. While previous studies in animal models and 2D culture systems have reported neurotoxic effects, few have addressed the region-specific vulnerability of the developing human brain. This study investigated the distinct effects of propofol on human dorsal (hCS) and ventral (hSS) forebrain organoids, uncovering region-specific differences in neuronal differentiation and maturation. Detailed electrophysiological analysis revealed that propofol enhanced neuronal activity-increased action potential frequency and amplitude-in hCS organoids. Transcriptomic analysis further indicated a metabolic shift away from hypoxic stress toward efficient aerobic pathways. These findings provide a deeper understanding of how anesthesia affects brain development, particularly in early stages, and highlight the importance of considering regional differences and longterm effects in future research.

Mononuclear palladium(I) halides are proposed intermediates in many palladium-catalyzed reactions. However, isolable examples of such species remain scarce. Herein, we report that 9,9-dimethyl-4,5-bis(di-tert-butylphosphino)xanthene ((tBu)Xantphos) ligand can effectively stabilize mononuclear palladium(I) halides. Mononuclear palladium(I) chloride [((tBu)Xantphos)PdCl] (1) was synthesized in 73% yield via the reduction of [((tBu)Xantphos)PdCl2] using excess potassium graphite (KC8) in THF under strictly controlled reaction time. Similarly, mononuclear palladium(I) bromide and iodide, [((tBu)Xantphos)PdBr] (2) and [((tBu)Xantphos)PdI] (3), were obtained with the yields of 68% and 42% respectively, through reduction of the reaction mixtures of [((tBu)Xantphos)PdCl2] with NaX (X=Br, I) with excess KC8. These three complexes are stable under nitrogen atmosphere and sensitive to air and moisture. Single-crystal X-ray diffraction studies revealed that all three complexes adopt a distorted T-shaped geometry, and the Pd-X bond lengths in [((tBu)Xantphos)PdX] (0.2469(2) nm, 0.2591(1) nm, and 0.2739(1) nm, for 1 similar to 3, respectively) are longer than those in the three-coordinate mononuclear palladium(I) halides [(dtbpf)PdX] (dtbpf = 1,1'-bis-(di-tert-butylphosphino)ferrocene) (J. Am. Chem. Soc. 2025, 147, 44552-44561.). The H-1 NMR spectra of these three complexes exhibit similar paramagnetically shifted signals as six broad peaks fall in the range of delta=0 similar to 20, while no P-31 NMR signal was observed. Electron paramagnetic resonance (EPR) spectroscopy recorded at 100 K indicated that g-factors of [((tBu)Xantphos)PdX] are g=[2.231, 2.079, 2.034] (X=Cl), [2.195, 2.081, 2.035] (X=Br), [2.201, 2.129, 2.074] (X=I), with hyperfine splitting constants attributed to the halogen atoms of A(X)=[33, 27, 90] MHz (X=Cl), [312, 75, 425] MHz (X=Br), [360, 150, 600] MHz (X=I). The g-values of [((tBu)Xantphos)PdX] are larger than those of [(dtbpf)PdX], whereas the hyperfine splitting constants A(P-31) is smaller and A(X) is larger. Density functional theory (DFT) calculations demonstrated that the singly occupied molecular orbitals (SOMOs) of 1 similar to 3 correspond to the antibonding interactions from the overlap of the dx2-y2 orbitals of palladium and the np orbitals of halogen. The calculated spin density on the palladium center decreases sequentially in complexes 1 similar to 3 (0.63, 0.61, and 0.57, respectively), which is larger than [(dtbpf)PdX]. On the other hand, the spin density on the halogen atoms increases correspondingly (0.17, 0.19, and 0.22, respectively), which is smaller than [(dtbpf)PdX]. Recently, Mirica and coworkers reported the mononuclear palladium(I) chloride [((tBu)Xantphos)PdCl] and bromide [((tBu)Xantphos)PdBr] (J. Am. Chem. Soc. 2025, 147, 41882-41896). While the structure and spectroscopic features of the two complexes in their report are nearly identical to what we observed here, they use cobaltocene as the reductant for the synthetic reactions and noted these compounds are unstable, which differ from our findings. Additionally, they did not achieve the synthesis of the iodide [((tBu)Xantphos)PdI] (3).

LL-D49194 alpha 1 (LLD) is a natural product with promising antitumor activity; however, its extremely low native fermentation yield has severely hindered further development. This study identified and characterized two key Streptomyces antibiotic regulatory protein-family activators (LldRg1, LldRg5) and a two-component system (LldRg3/Rg4) within its biosynthetic gene cluster. Coordinated overexpression of these three regulators dramatically increased LLD titer >100-fold to similar to 400 mg/L. This engineering also led to the coupregulation of an MFS transporter and a DNA repair-related self-resistance gene, suggesting a concerted activation of efflux and self-defense mechanisms alongside biosynthetic enhancement. Our work establishes an efficient microbial cell factory for LLD and demonstrates a generalizable strategy for enhancing the production of valuable, highly cytotoxic natural products.

Tetrafluoroethylene (-CF2CF2-) is a privileged motif in materials and medicinal chemistry. However, a highly modular and synthetically convenient method for constructing the CF2CF2 linkage remains elusive. Here, we report an unprecedented copper-catalyzed, bench-friendly difluorocarbene elongation platform that converts BrCF2CO2K, silyl enol ethers, and secondary propargyl sulfonates into tetrafluoroalkylated allenes in a single operation. Simply tuning the difluorocarbene stoichiometry switches selectivity to the corresponding monodifluoromethylene (CF2) incorporation products. The method is modular (no preformed fluorinated building blocks are required), operationally simple (all reagents are commercially available or easily prepared), highly selective (controllable formation of bis- or mono-CF2-containing products), and tolerant of diverse functional groups, including those found in drug-like scaffolds. The products serve as versatile linchpins for downstream transformations, opening expedient routes to advanced materials and modern drug discovery.

This paper reports a synthetic method for the rapid construction of dibenzobicyclo[2.2.2]octane frameworks through an intramolecular [4 + 2] dearomative cycloaddition reaction under catalyst-free conditions. Utilizing anthracene-tethered vinylidenecyclopropane derivatives (Anth-VDCPs) as substrates, the reaction proceeds under mild heating conditions, demonstrating excellent functional group tolerance and delivering the target products in moderate to excellent yields. Notably, two distinct cycloaddition products can be selectively formed by strategically varying the reaction temperature and substituent positions on the anthracene core. The large-scale synthesis and synthetic transformations of the products were also demonstrated. DFT calculations rationalized the reaction mechanism and the origin of regio-selectivity of the products.

A general method for catalytic enantioselective borylation and silylation of ketimines remains elusive due to their extenuated electrophilicity, the difficulty to discriminate the two non-hydrogen substituents on carbonyl groups stereoselectively, and the lability of products. Herein, based on a series of newly developed chiral NHCs, such a general method is developed. In the presence of a 1 mol % copper-YC-NHC3 complex, the borylation of ketimines works smoothly to provide a broad range of alpha-amino tertiary boronates in moderate to high yields with high enantioselectivity. The silylation of ketimines is accomplished with high enantioselectivity in the presence of a 5 mol % copper-YC-NHC11 complex. In light of the calculated percent buried volumes with CuCl-YC-NHC1 and CuCl-YC-NHC11 complexes using SambVca software, YC-NHCs are found to possess fewer crowded chiral pockets around the Cu(I)-metal center than common NHCs. On the basis of DFT calculations and a classic quadrant model, the confined steric environment leaves only the first quadrant accessible for substrate approach, directing nucleophilic attack from the Re face of the ketimine while rendering the competing Si face pathway kinetically disfavored. Finally, the synthetic utilities of both the borylation and the silylation products are showcased by several transformations.

PIEZO channels are critical for sensory mechanotransduction. While MyoD- family inhibitor proteins were identified as PIEZO1 auxiliary subunits, their broader regulatory roles, particularly in sensory cells, remained unclear. Here, we demonstrate native MDFIC and MDFI regulate endogenous PIEZO channel currents in various nonsensory cell types. However, neither MDFIC nor MDFI are expressed in primary sensory neurons. In these cell types, we identified an uncharacterized third member of this family, Mdfic2/Gm765, that shares the ability to physically bind to PIEZO1 and PIEZO2. MDFIC2 is selectively expressed in subsets of mechanosensitive neurons, including dorsal root ganglia, trigeminal ganglia, and vagal sensory neurons. Like its paralogues, MDFIC2 alters PIEZO1/2 mechanosensitivity and inactivation kinetics, converting them into high- threshold slowly inactivating mechanoreceptors. Extensive cryo- EM reveals a conserved binding pocket for these auxiliary subunits in the pore modules of both PIEZO1 and PIEZO2 mediated by the posttranslationally modified distal C termini of MyoD- family inhibitor proteins. This structural and functional characterization of MyoD- family inhibitor proteins as PIEZO1/2 channel auxiliary subunits offers insights into the mechanobiology of nonsensory and sensory cells.

Evasion of cell death is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation-and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. Our bodies are made of cells that live, and just as surely, of cells that must die. -S. Brenner