Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α', is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it an attractive therapeutic target. We report a medicinal chemistry campaign that delivered an imidazotriazine pan-CK2 series culminating in BMS-135 and its phosphate prodrug BMS-159. Structure-guided design enabled a scaffold hop from imidazopyridazine to imidazotriazine that improved kinome selectivity while preserving critical hinge and Lys68 interactions. Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 N-ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development.

Organophosphorus compounds constitute an important class of phosphorus-containing molecules that are widely encountered in agrochemicals, pharmaceuticals, functional materials, and ligand frameworks. Consequently, the development of green and efficient methods for their synthesis has attracted considerable attention from the synthetic community. This review systematically summarizes methodological advances from 2020 to 2025 in the electrochemical synthesis of organophosphorus compounds from readily accessible P-H reagents, including dialkyl phosphonates and diphenylphosphine oxides, with selected early 2026 publications also included to ensure comprehensive coverage of the field. The content is organized into four main sections according to bond-forming patterns: P-C, P-N, P-O, and P-X (X = S, Se, F) bond formation. Mechanistically, these reactions are broadly classified into three pathways: (1) direct nucleophilic attack of P-H reagents on electrochemically generated electrophilic intermediates; (2) iodide-mediated processes involving formation of highly electrophilic phosphorus intermediates; and (3) radical pathways featuring phosphorus-centered radicals. Finally, current challenges and future opportunities are discussed.

Comprehensive Summary Redox‐active ligands on transition metals have been shown to provide access to biradical reaction pathways, however the corresponding reaction pathway for main group systems is not known. The compound ((2,6‐ i Pr 2 C 6 H 3 )NC(Me)) 2 AlCl(THF) 1 reacts with aldehyde or ketone effecting SET and prompting C−C coupling to afford diradical products. However, the corresponding reactions with 2,2,6,6‐tetramethylpiperidine‐ N ‐oxide, azides and diazomethanes proceed to give products derived from both single electron transfer (SET) and hydrogen atom transfer (HAT). Computations show that these latter products are formed via initial SET affording a biradical intermediate which prompts HAT.

2,6-Difluorination alters the supramolecular packing of a lactam-phenylalanine dipeptide, changing the non-fluorinated lamellar arrangement into a compact helical packing architecture. The resulting assemblies exhibit enhanced magnetic-field-assisted orientation during deposition and drying.

Dioxygen activation by a bioinspired FeZn4(prv)4(btdd)3 MOF to form high-spin (S = 2) iron(IV)-oxo active species was revealed to proceed via two-state reactivity. The iron(IV)-oxo species containing the Lewis acid Zn2+ cation hydroxylates cyclohexane with an energy barrier of only 15.1 kcal mol-1, which is reminiscent of the indispensable role of the Ca2+ ion in the PSII system.

Bioorganic molecules, such as amino acids, nucleobases, and sugars, are widely distributed in space. Here, we utilized the Chinese Space Station to carry out an investigation on the solid-state condensation reactions of these "prebiotic organic molecules" under the combined effects of ionizing radiation and forsterite. Cumulative low-dose ionizing radiation can trigger dipeptide formations and phosphorylation of riboses. Dipeptide yields increased 41-fold due to the synergistic effect of forsterite plus sodium trimetaphosphate (P3m). P3m is activated upon irradiation to phosphorylate nucleosides into nucleotides. Under ionizing radiation, forsterite can promote hydroxyapatite to serve as an accessible phosphorus source for activating amino acids to form peptides. These findings indicate that complex biomolecules can be formed abiotically in space through ionizing radiation activation with the assistance of forsterite in certain radiation - resistant environments distant from planetary surfaces. It implies that apart from transporting prebiotic organic molecules to Earth, space can also provide opportunities for the in-situ assembly of ordered biomolecules from these disordered materials.

Accumulating evidence indicates that a hypomagnetic field (HMF, <5 μT) has a significant impact on various organ systems in animals. However, the cellular and molecular mechanisms underlying these biological effects remain unclear. Understanding the molecular mechanisms underlying mammalian responses to a HMF is crucial for addressing health and safety concerns associated with HMF exposure. In this study, we investigated the changes in intracellular protein phosphorylation under HMF conditions and validated the functional mechanisms by which HMF-induced protein phosphorylation affects cell behavior. We found that U2OS cells can rapidly sense changes in magnetic fields, leading to alterations in protein phosphorylation levels within the cell. The quantitative phosphoproteomics results revealed that the exposure of U2OS cells to the HMF environment for 0.5 h and 3 days resulted in the alteration of 1101 and 1543 phosphosites, respectively. Notably, HMF exposure enhanced the phosphorylation of β-Catenin at Ser552, and this increased phosphorylation-promoted U2OS proliferation and migration. Furthermore, quantitative proteomics showed that exposure to a HMF for 3 days upregulated the expression of LOX and FN1, while the knockdown of LOX or FN1 suppressed the proliferation and migration of the U2OS cells. These results suggest that a HMF enhances U2OS cell proliferation and migration by promoting β-Catenin phosphorylation and upregulating FN1 and LOX expression.

Considering that Mars mission plans exceed 1,000 days, the maintenance of astronauts' digestive health during the extended work periods in orbit is worthy of extensive attention. In this study, we discovered that simulated microgravity (SMG) induces damage in GES-1 cells, including the accumulation of ROS (by 1.2-fold), abnormal cell apoptosis (occurring 3.4 times), and the destruction of cell tight junctions, with Occludin expression decreased by 31.77 ± 0.11% and cell permeability increased by 16.85 ± 7.76%. The proportion of N-glycan core fucosylation visibly increased in GES-1 cells treated with SMG. Magnesium ascorbyl phosphate (MAP), a phosphorus-containing nutritional supplement, can relieve SMG-induced damage in GES-1 cells, restoring cellular activity and tight junctions. Our research not only offers an alternative strategy for maintaining the health of astronauts in orbit but also creates new opportunities for space food processing and the alleviation of gastric disorders, which serves as an inspiration for the future of space exploration.

A radical-involved cascade reaction provides straightforward and efficient access to structurally complex building blocks from readily available substrates. Herein, we report an unprecedented electrochemical synthesis of 3,3'-bisoxindoles through three newly formed C-C bonds enabled by alternating current polarity, which obviates the need for external oxidants and showcases excellent chemoselectivity.

Bismuth (III) chloride (BiCl3) has emerged as a powerful and ecofriendly Lewis acid catalyst in modern organic synthesis. Distinguished by its low toxicity, affordability, and environmental compatibility, BiCl3 offers an attractive alternative to conventional metal catalysts. This review compiles and summarizes the significant findings reported to date on the diverse applications of BiCl3 in promoting diverse organic transformations including oxidation, reduction, bond-forming reactions (C–C, C-N, C-P, C-O, C-S, and C-X), and deprotection strategies. Its effectiveness under mild, solvent-free, and even microwave-assisted conditions underscores its potential in green chemistry. The ability of BiCl3 to deliver high yields with good selectivity and reusability positions it as a catalyst of growing importance in sustainable synthetic methodologies.

The abiotic formation of peptides in water remains a fundamental challenge in origin-of-life research. Direct aqueous condensation of amino acids is thermodynamically hindered; consequently, existing models frequently depend on activation agents or require extreme conditions. We have developed and implemented an aqueous pathway for peptide synthesis mediated by carbamoyl phosphate (CAP) within a mild, “warm little pond” scenario. Co-incubation of diverse proteinogenic amino acids with CAP and metal cations promoted peptide bond formation. Our analysis reveals that magnesium ions operate synergistically with CAP, driving a dual-activation mechanism through N-carbamoylation and O-phosphorylation intermediates. Crucially, we establish that CAP can be generated in situ directly from early-Earth accessible precursors, urea and orthophosphate. This continuous aqueous pathway entirely bypasses the necessity for destructive dry-state cycles. CAP continues to play a vital role in nitrogen metabolism and the de novo synthesis of pyrimidine nucleotides in extant organisms. Therefore, we suggest that CAP serves as an evolutionary bridge, linking primordial geochemical conditions to the emergence of functional biochemical machinery. The abiotic formation of peptides in water is a key challenge in origin-of-life research due to thermodynamic constraints. Here, the authors demonstrate a mild aqueous pathway for peptide synthesis using carbamoyl phosphate (CAP), revealing a dual-activation mechanism with magnesium ions, suggesting CAP as an evolutionary link to early biochemical processes.

Nitrogen-containing heterocycles constitute the pharmacophoric core of the majority of clinically approved small-molecule drugs, yet their conventional synthesis relies on scaffold-specific condensation routes that are poorly suited to late-stage structural diversification. The emergence of single-atom skeletal editing, where one nitrogen atom is inserted directly into an intact aromatic ring to transform scaffold identity without rebuilding the molecular periphery, represents a fundamental departure from traditional heterocycle synthesis and provides a powerful new retrosynthetic logic for medicinal chemistry. This review surveys significant advances in nitrogen atom insertion into aromatic N-heterocycles reported between 2015 and 2025, organized by mechanistic platform. We discuss nitrene-mediated insertion using iodonitrene and sulfenylnitrene reagents, transition-metal-catalysed strategies including copper- and cobalt-catalysed ring expansions and carbon-to-nitrogen transmutation of arenols, electrochemical approaches that eliminate stoichiometric oxidants, and emerging photochemical and photolytic methods that enable late-stage modification of complex substrates. For each platform, substrate scope, functional group tolerance, mechanistic underpinning, and practical limitations are critically evaluated. We further highlight how these strategies collectively enable nitrogen scanning in drug discovery, the systematic replacement of carbon with nitrogen within a lead scaffold to modulate potency, selectivity, and pharmacokinetic properties. Key open challenges including enantioselective nitrogen insertion, predictive regioselectivity, and scalable sustainable synthesis are outlined alongside future directions for this rapidly evolving field.

Axially chiral allenes are valuable motifs in natural products and chiral ligands in asymmetric catalysis, yet methods to access enantioenriched difluoromethylated analogues remain undeveloped. Here we report the efficient copper-catalyzed SN2'-type substitution of propargylic alcohol derivatives with Zn(CF2H)2(DMPU)2, to deliver enantioenriched difluoromethylated allenes under mild conditions. This transformation proceeds with high regioselectivity, a broad substrate scope, and operational simplicity, providing a general strategy to construct CF2H-substituted chiral allenes of potential relevance to drug discovery.

Objective Microgravity-induced neural dysfunction poses a critical risk during long-term spaceflight. However, the intrinsic mechanosensing mechanisms by which neural stem cells (NSCs) decode gravitational loss into biochemical responses and effective multi-target countermeasures remain elusive. This study aims to clarify the protective mechanism of ginsenoside Rg1 (Rg1) on simulated microgravity (SMG)-damaged C17.2 mouse neural stem cells (NSCs) by targeting vimentin serine 56 (Ser56) phosphorylation and the mitogen-activated protein kinase (MAPK)/protein kinase B (AKT) signaling network, and verify its “multi-pathway synergy” characteristic guided by traditional Chinese medicine (TCM) theory. Methods An SMG environment was established using a random positioning machine (RPM). The safe and effective concentration of Rg1 (40 μmol/L) was screened using the cell counting kit-8 (CCK-8) assay. Mitochondrial function and cytoskeletal structure were evaluated via transmission electron microscopy and F-actin staining. Flow cytometry, Western blotting, quantitative real-time polymerase chain reaction, combined with global proteomics, phosphoproteomics, and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor experiments, were employed to dissect the action mechanism of Rg1. Results First, SMG inhibited NSC differentiation, disrupted cytoskeletal structure, and induced apoptosis, with the core mechanism being the impairment of cytoskeletal architecture and its dynamic phosphorylation network. Second, 40 μmol/L Rg1 restored F-actin continuity, rescued neurodifferentiation function, and inhibited apoptosis; these effects relied on the activation of the MAPK/AKT kinase network and the specific rescue of vimentin Ser56 phosphorylation. Third, Rg1 regulated the kinase-intermediate filament (IF) axis through “ERK1/2-dependent and independent” dual pathways rather than single-target intervention. Notably, its regulatory effect directly acted on post-translational modification (phosphorylation) instead of merely altering protein abundance. Conclusion Rg1 restores cytoskeletal integrity and neurogenesis in C17.2 NSCs under SMG by regulating the kinase-IF axis. This modern molecular evidence bridges TCM theory with mechanobiology, confirming Rg1 as a promising TCM candidate for protecting astronaut brain health. It exemplifies the “holistic regulation” of TCM and provides a paradigm for the application of TCM in space medicine.

The evolutionary origin of copper-binding proteins remains a central question in prebiotic chemistry. Modern copper proteins predominantly coordinate copper through histidine and cysteine residues, suggesting that these amino acids were selectively favored during early protein evolution. Here, we propose that ultraviolet (UV) radiation acted as a key selective factor in shaping primordial copper-peptides. Spectroscopic analyses suggest that His2 interacts with Cu(II) through contributions from both its N- and C-terminal donor groups, generating a comparatively stronger binding environment and supporting its plausibility as a primitive Cu-binding motif. Yet His2 is intrinsically vulnerable to UV-induced degradation, highlighting the need for stabilizing partners. In contrast, Tyr2 exhibits remarkable photostability and preferentially binds Cu(II) through its N-terminal, consistent with a second-shell protective role analogous to those observed in modern Cu-binding proteins. Together, these findings suggest that Earth’s UV-rich environment favored cooperative copper-binding dipeptides, where His₂ provided catalytic functionality while Tyr2 contributed photostability, establishing a plausible pathway from simple Cu-peptide complexes to functional metalloenzymes.

Conspectus A central question in origin-of-life research is how biological macromolecules and cellular structures arose from simple precursors under prebiotic conditions. This review focuses on the chemical evolution model of N-phosphoryl amino acids (NPAAs) and their multifaceted roles in this process. Featuring high-energy P–N bonds, NPAAs enable intramolecular activation via pentacoordinate phosphorus intermediates, facilitating the formation of homochiral peptides and nucleotides under mild aqueous conditions. Moreover, N-amino acid-nucleotide conjugates (N-aa-NMPs) drive peptide formation with chiral selection between amino acids and nucleosides, where the peptide yield for each amino acid is modulated by specific nucleosides, thereby laying a foundation for a proto-genetic code. Additionally, amphiphilic NPAA derivatives spontaneously self-assemble into vesicles and selectively condense peptides at membrane interfaces, whereas the in situ generation of N-fatty acyl amino acids further enhances membrane stability. Collectively, these findings support a phosphorus-centered model for the integrated origin of nucleic acids, proteins, and membranes.

We report a dual nickel/photoredox-catalyzed three-component phosphonylacylation of various alkenes using readily accessible substrates and commercially available catalysts, delivering structurally diverse γ-ketophosphine oxides in one pot through concurrent C-P/C-C bond formation. This operationally simple strategy also provides efficient access to natural molecule- and pharmaceutical-containing γ-ketophosphine oxide analogues and features mild reaction conditions, a broad substrate scope, high regioselectivity, and moderate to excellent yields.

Lightning-sea interactions generate plasma bubbles that act as electrochemical reactors, producing amino acids, nucleobases, and peptides with yields 100-300% higher than spark discharges. This process accelerates carbon-nitrogen coupling and enhances biogeochemical cycling, linking CO2 and NH3 to bioavailable organic compounds.

The search for extraterrestrial life represents one of humanity’s most profound scientific endeavors. This review examines the role of prebiotic chemistry in our quest to detect extraterrestrial life. Analyzing diverse chemical pathways, including the Strecker synthesis, cyanide polymerization, and Fischer–Tropsch-type reactions, outlines how simple inorganic precursors may evolve into complex chemical reaction networks under non-biological conditions. While compounds such as amino acids are common in both abiotic and biotic contexts, discerning their origins requires an understanding of reaction mechanisms, environmental contexts, and the thermodynamic challenges of polymerization. Moreover, this review addresses the emergence of homochirality and the development of genetic systems, proposing that these phenomena may arise from dynamic prebiotic processes. Laboratory simulations of extraterrestrial environments are crucial in testing these hypotheses, providing insights into the potential trajectories from simple monomers to complex macromolecules under planetary surface and interstellar conditions. Ultimately, this review advocates for reassessing biosignature interpretation methods, underscoring the need for integrated, multifaceted approaches that consider both prebiotic chemical evolution and environmental context when evaluating the potential for life beyond Earth.

A series of α-diimine-supported, spiro-Al2E2-bridged diradicaloids (E = S, Se or NPh) were isolated from reactions of LAl(thf)Cl with S8, Se and LiNHPh, respectively. Each species features a ligand-centered, open-shell singlet diradical ground state with a small singlet-triplet energy gap.