A zinc(II)-catalyzed cycloisomerization of bis(indol-3-yl)-ynamides in the presence of water has been established for constructing carbonyl-containing bisindole derivatives in moderate to good yields with good functional group tolerance and a broad substrate scope. The reaction proceeds through a 7-endo-dig cyclization followed by a pseudo-1,6-indole-migration, which is supported by isotope 18O-labeling experiments. Moreover, large-scale synthesis and further synthetic transformation of the obtained product have been also presented.

In this paper, we reported a palladium-catalyzed rapid construction of oxabicyclo[3.2.1]octane skeletons through an intermolecular [3 + 4] cycloaddition of vinylidenecyclopropane-diesters (VDCP-diesters) with pyrroles and indoles bearing a trifluoroacetyl group at the 2-position under mild conditions. This cycloaddition proceeds through a key zwitterionic pi-propargyl palladium species derived from a VDCP-diester, affording the corresponding cycloadducts in moderate to good yields and ee values, along with good substrate applicability. The strong electron-withdrawing effect of the trifluoroacetyl group is essential for this [3 + 4] cycloaddition reaction. Replacing it with other acyl groups triggers the reconstruction of the cyclopropane ring to produce a series of vinylcyclopropane products (VCP products) through a hydroamination reaction pathway. The plausible reaction mechanisms are proposed on the basis of control and deuterium-labeling experiments as well as a Fukui function analysis.

Cobalt-catalyzed enantioselective electroreductive cross-coupling of aryl iodides and indole bromides has been developed. This strategy is characterized by mild reaction conditions, high enantioselectivities, and a broad substrate scope. Notably, this approach effectively addresses the challenges associated with indole substrates that do not possess electron-withdrawing substituents at the 2-position, a limitation that remains unresolved in other strategies.

Here we report an unprecedented mechanism involving the thermolytic homolysis of difluoroalkylpalladium species, which can be directly generated in situ from palladium difluorocarbene, yielding difluoroalkyl radicals. This discovery bridges the gap between difluorocarbene and fluorocarbon radical, enabling difluorocarbene to function as both a fluorocarbanion and a fluorocarbon radical precursor. By exploiting the synthetic versatility of difluorocarbene to sequentially form various active intermediates, including palladium(II) difluorocarbene, difluoroalkylpalladium species, and difluoroalkyl radicals, this strategy provides a synthetically versatile paradigm for the modular construction of difluoroalkylated arenes. The approach leverages readily available components, including aryl iodides, alkenes, and the industrial chemical ClCF2H, opening a new avenue for the precise introduction of the difluoromethylene group.

We pioneered a donor-sensitizer-acceptor three-component system to devise organic long persistent luminescence (OLPL) materials, where the afterglow color is solely determined by sensitizer's emission color. Here we report two major breakthroughs in the field of OLPL: 1) tailored fabrication of pure-blue OLPL materials and 2) a direct observation of OLPL erased by green/red lights. We rationally designed blue thermally activated delayed fluorescence (TADF) sensitizers by connecting biphenyl-containing group with suitable HOMO and T-1 energy levels to difluoroboron beta-diketonate moiety based on the energy gap law and the El-Sayed rule. The resultant donor-sensitizer-acceptor three-component materials exhibit pure-blue hour-long OLPL afterglow with lambda(OLPL) < 450 nm; such pure-blue OLPL materials remain elusive in the reported studies. Mechanistic investigations confirm a unique charge-separation-induced OLPL pathway, involving electron transfer processes between donor, sensitizer, and acceptor. The OLPL materials are UV/visible-light-excitable. Remarkably, it is found that the OLPL emission can be erased by green or red light; the long-lived excited TADF sensitizers can be pushed by green/red lights to higher excited states, followed by fast nonradiative deactivation, enabling optical erasure. This unprecedented optical write-erase functionality, coupled with hour-long OLPL duration, would offer promising opportunities for rewritable photonic storage, encryption, and dynamic labeling applications.

NMNAT2 is an essential but labile protein required for axon integrity. It is rapidly degraded after nerve injury, promoting axon degeneration. However, the mechanisms regulating NMNAT2 ubiquitination and turnover in neurons remain unclear. In this study, we identify the F-box protein FBXO21 as an NMNAT2-binding protein, and its deficiency confers axonal protection via increasing NMNAT2 abundance. FBXO21 recruits SKP1, CUL1, and RBX1 to form an SCFFBXO21 complex, which promotes NMNAT2 ubiquitination in vivo and in vitro. SCFFBXO21 ubiquitinates NMNAT2 at K155 within an isoform-specific targeting and interaction domain of the family of NMNATs, which underlies the unique labile nature of NMNAT2. The ubiquitination-deficient NMNAT2-K155R exhibits substantially reduced protein turnover and enhanced axon-protective capacity. Finally, in Fbxo21 knockout mice, NMNAT2 levels are markedly increased and the survival of injured sciatic nerves is significantly prolonged. Collectively, our findings reveal a crucial role of FBXO21 in axon degeneration, highlighting the SCFFBXO21 complex as a potential target for modulating NMNAT2-dependent axon survival.

The extremely limited energy density and leakage risks of liquid electrolytes in supercapacitors have hindered their widespread industrialization. In this study, a novel cross-linked gel polymer electrolyte was designed and prepared by incorporating redox-active units to enhance energy density and address leakage issues in supercapacitors. These quasi-solid-state redox-active electrolytes (DCBQ@PVA) were synthesized through nucleophilic functionalization of a polyvinyl alcohol (PVA) matrix with dichlorobenzoquinone (DCBQ) redox crosslinkers. Electrolyte membranes were fabricated via solution casting, and their performance was systematically optimized. As expected, the DCBQ@PVA gel electrolyte significantly improved the electrochemical performance of quasi-solid-state supercapacitors, expanding the voltage window from 1.0 V to 1.8 V, increasing the specific capacitance from 27 F g-1 to 43 F g-1, and ultimately achieving a fivefold enhancement in energy density (up to 18.8 Wh kg-1).

Drug resistance remains one of the biggest challenges in kinase inhibitor therapy, particularly in cancers where prolonged treatment fosters the emergence of resistant mutations. These mutations often alter amino acid residues within the kinase active site, reshaping the local chemical environment and disrupting critical drug-target interactions. The resulting changes - such as steric hindrance, loss of key hydrogen bonds, elimination of reactive residues, or other structural incompatibilities - can drastically reduce drug efficacy. To counter these effects, drug molecules must undergo tailored chemical adaptation - strategic modifications that align their molecular features (e.g., geometric shape, stereochemistry, acidity/basicity, and reactivity) with the mutation-altered changes in steric, electronic, and reactivity landscapes within the mutant kinase binding pocket. In this Account, we describe how the principles of chemical adaptation guided our rational design of small molecule kinase inhibitors to overcome clinically relevant resistance. Over the past 18 years, these efforts have culminated in the discovery and approval of two targeted therapies - olverembatinib and limertinib - as well as the advancement of several clinical-stage candidates.Olverembatinib was developed to treat chronic myeloid leukemia patients harboring the gatekeeper Bcr-AblT315I mutation, which confers resistance to first- and second-generation inhibitors. To mitigate steric clashes and restore lost hydrogen bonding, we introduced an alkyne linker to accommodate conformational shifts, and a 1H-pyrazolo[3,4-b]pyridinyl moiety to form new stabilizing hydrogen bonds within the hinge region. For non-small cell lung cancer patients with EGFRT790M-driven resistance, we designed heterocyclic scaffolds bearing electrophilic groups capable of covalently targeting Cys797, enabling high selectivity for EGFR mutants while sparing wild-type EGFR. This approach led to the development of limertinib, a potent and mutant-selective third-generation EGFR inhibitor approved for treating patients with or without EGFRT790M mutations, including those with brain metastases. Building on this success, we are advancing next-generation inhibitors designed to overcome additional resistance mutations such as EGFRL858R/T790M/C797S.In summary, this Account highlights the medicinal chemistry strategies underlying the approvals of olverembatinib and limertinib, illustrating how chemical adaptation can be harnessed to overcome kinase inhibitor resistance. Moving forward, we aim to expand this concept across broader drug modalities and therapeutic targets to address ongoing clinical challenges.

Structurally well-defined mononuclear Pd(I) complexes are exceedingly rare and their reactivity remains poorly understood. Herein, the reactivity of the Pd(I) amido complex [(BINAP)Pd(NHArTrip)] (1, BINAP = 2,2 '-bis(diphenylphosphino)-1,1 '-binaphthalene, ArTrip = 2,6-bis(2 ',4 ',6 '-triisopropylphenyl)phenyl) toward organic halides has been investigated. Complex 1 reacts with benzyl bromides in single-electron redox reaction mechanism to furnish the Pd(II) amido complex [(BINAP)Pd(Br)(NHArTrip)] (2) along with benzyl radical, whereas its reactions with aryl and alkyl iodides result in Pd-N bond cleavage, generating the aminyl radical [NHArTrip]center dot and Pd(0) species that subsequently performs oxidative addition reactions with organic iodides to yield organo-Pd(II) species.

Sulfinamides, pivotal scaffolds in modern organic synthesis, have undergone a continuous evolution of synthetic methodologies over the past century, yet the precise construction of sulfur stereocenters remains a significant synthetic challenge. Herein, we report a versatile catalytic asymmetric strategy for the synthesis of S-chirogenic allyl sulfinamides through the direct allylation of sulfinylamines with allenes. Our methodology employs a catalytic system comprising copper salts, hydrosilanes, and readily accessible chiral ligands, which facilitates the in situ generation of organocopper surrogates via hydrocupration of allenes. This approach demonstrates remarkable substrate scope and excellent regio-, stereo-, and enantioselectivity across a diverse array of sulfinamide products. Comprehensive mechanistic investigations, including detailed experimental studies and computational analyses, have been conducted to elucidate the reaction pathway and identify the key factors governing enantioselectivity.

The protein-kinase-like superfamily proteins are crucial and generally catalyse substrate phosphorylation using adenosine 5 '-triphosphate. Pseudokinases are non-canonical protein-kinase-like members deficient in kinase activity, and few of them are known to be enzymatically active and to have catalytic ability rather than phosphorylation. Based on biosynthetic investigations into thioamitides and lanthipeptides-two different families of ribosomally synthesized and post-translationally modified peptides-we here report a peptide cyclization activity of pseudokinases (TvaE and SacE) that enables (ene)thioether residue formation. We determine the dedicated cyclase activity in unsaturated 2-aminovinyl-cysteine formation and mine for similar activity in saturated lanthionine formation. Biochemical characterization, heterologous expression, co-crystallization, computational analysis, genome mining, isotope labelling and site-specific mutagenesis rationalize the commonality in catalysis, demonstrating that a protein-kinase fold can be repurposed for unexpected utilities. Related cyclases differ from known enzymatically active pseudokinases that resemble canonical protein-kinase-like proteins in mechanism and function. Instead, they catalyse Michael addition for (ene)thioether crosslinking through a sandwich-like substrate-assisted process.

The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adeno-sylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.

The canonical necrosome formed by receptor-interacting protein kinase 1 (RIPK1) and RIPK3 is a functional amyloid fibril structure critical to intracellularly drive necroptosis. Since necroptosis leads to the release of intracellular content, the fate of RIPK1/RIPK3 fibrils after necroptotic cell death has not been investigated. Here, we tracked RIPK1 and RIPK3 coassemblies and found that these fibrillar aggregates could be released into the culture medium after the membrane rupture in necroptotic cells. Interestingly, these RIPK1/RIPK3 fibrils were capable of infiltrating recipient cells and acting as seeds for the nucleation and formation of the endogenous necrosome. Cryo electron microscopy structural analysis unveiled a distinctive S-shaped conformation common to RHIM fibrils of RIPK1 and RIPK3, which can facilitate the cross-seeding of RIPK3 by RIPK1 or RIPK1/RIPK3 fibrils. Our findings suggest the ability of functional RIPK1/RIPK3 amyloid fibrils in intercellular spreading to induce protein conformation change in recipient cells and provide structural insights into the mechanism of RIPK1 and RIPK3 cross-templating to drive necroptosis.

Amyloid fibrils, defined by their cross-beta architecture, are central to both disease and function, yet the molecular principles governing their formation remain incompletely understood. Ninjurin-1 (NINJ1), a membrane protein essential for plasma membrane rupture (PMR) during cell death, contains an N-terminal amphipathic alpha-helix. Here, we investigate a key peptide fragment of this region (residues 40-69, HE30) and uncover its membrane-disruptive activity, self-assembly, and structural transitions. Monomeric HE30 reorganizes lipids to induce membrane thinning while undergoing an environmentally responsive alpha-helix-to-beta-sheet transition that drives amyloid fibril formation. Fibrils formed at physiological temperatures are predominantly nontwisted, but elevated temperatures induce left-handed twisted structures with variable pitches and lengths, and even result in high-order superhelical bundles. We further resolved the twisted fibril structures of HE30 by cryo-EM, revealing two distinct fibril polymorphs stabilized by both hydrophobic and electrostatic interactions. Consistently, salts inhibit HE30 fibrillation, emphasizing the role of electrostatic interactions in stabilizing fibrils. Moreover, acidic conditions (similar to pH 4.4) promote fibril formation, whereas alkaline conditions lead to disassembly into alpha-helical monomers in a reversible manner. In situ AFM tracking reveals the asymmetric growth of fibrils, where one end elongates faster and the opposite end exhibits slower growth or complete inhibition. Functionally, HE30 fibrils are nontoxic and act as scaffolds for the temperature-controlled assembly of gold nanoparticle (AuNPs) superstructures. These findings not only advance our understanding of NINJ1-induced PMR but also provide a detailed structural basis for HE30 fibril formation via alpha-helix to beta-sheet transitions and underscore their potential as building blocks for fibril-based biomaterials.