A gold-catalyzed oxidative cyclization/nucleophilic addition/C-C bond cleavage reaction of ynones with various nucleophiles has been developed. This methodology allows for the formation of highly functionalized linear N-Ts amides with broad substrate scope, high efficiency, and general tolerance of functional groups. A wide range of nucleophiles such as alcohols, water, and amines including aryl and alkyl amines are compatible with the current method. The C-C triple bond cleavage of the ynone substrate was observed during the process.

Stereochemical enrichment of a racemic mixture by deracemization must overcome unfavorable entropic effects as well as the principle of microscopic reversibility; recently, photochemical reaction pathways unveiled by the energetic input of light have led to innovations toward this end, most often by ablation of a stereogenic C(sp(3))-H bond. We report a photochemically driven deracemization protocol in which a single chiral catalyst effects two mechanistically different steps, C-C bond cleavage and C-C bond formation, to achieve multiplicative enhancement of stereoinduction, which leads to high levels of stereoselectivity. Ligand-to-metal charge transfer excitation of a titanium catalyst coordinated by a chiral phosphoric acid or bisoxazoline efficiently enriches racemic alcohols that feature adjacent and fully substituted stereogenic centers to enantiomeric ratios up to 99:1. Mechanistic investigations support a pathway of sequential radical-mediated bond scission and bond formation through a common prochiral intermediate and reveal that, although the overall stereoenrichment is high, the selectivity in each individual step is moderate.

Dopant-matrix organic afterglow materials exhibit ease of fabrication and intriguing functions in diverse fields. However, a deep and comprehensive understanding of their photophysical behaviors remains elusive. Here we report manipulation of a room-temperature phosphorescence/thermally activated delayed fluorescence (RTP/TADF) afterglow mechanism via the mismatch/match of intermolecular charge transfer between dopants and matrices. When dispersed in inert crystalline matrices, the luminescent dopants show RTP lifetimes up to 2 s. Interestingly, when suitable organic matrices are selected, the resultant dopant-matrix materials display a TADF-type afterglow under ambient conditions due to the formation of dopant-matrix intermolecular charge transfer complexes. Detailed studies reveal that reverse intersystem crossing from dopants' T-1 states to charge transfer complexes' S-1 states, which features a moderate k(RISC) of 10(1)-10(2) s(-1), is responsible for the emergence of a TADF-type organic afterglow in rigid crystalline matrices. Such less reported delicate photophysics reveals a new aspect of the excited state property in dopant-matrix afterglow systems.

A nickel-catalyzed direct reaction of allylic alcohols with easily accessible alkenyl boronates has been developed, which provides valuable 1,4-dienes with high regio- and stereoselectivity in good to excellent yields, wide substrate scope, and functional group compatibility. The catalytic system simply consists of Ni-(cod)(2) as the catalyst and a ligand, without a need for a base and alcohol activator in most cases. The proper choice of ancillary ligands is highly important for this reaction. Depending on the substitution pattern of allylic alcohols and/or alkenyl boronates, different ligands were used for improving the reaction efficiency.

Reported herein is an unprecedented protocol for C(sp3)-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed. Decarboxylative radical phosphinylation of N-acyloxyphthalimides with aryl- or alkylphosphonites has been accomplished under metal-free conditions. An unprecedented mechanism involving the formation and subsequent oxidation of phosphoranyl radicals is proposed.image

Detecting exosomal markers using laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) is a novel approach for examining liquid biopsies of non-small cell lung cancer (NSCLC) samples. However, LDI-TOF MS is limited by low sensitivity and poor reproducibility when analyzing intact proteins directly. In this report, gold nanoparticles/cellulose nanocrystals (AuNPs/CNC) is introduced as the matrix for direct analysis of intact proteins in NSCLC serum exosomes. AuNPs/CNC with dual dispersion effects dispersed and stabilized AuNPs and improved ion inhibition effects caused by protein aggregation. These features increased the signal-to-noise ratio of [M+H]+ peaks by two orders of magnitude and lowered the detection limit of intact proteins to 0.01 mg mL-1. The coefficient of variation with or without AuNPs/CNC is measured as 10.2% and 32.5%, respectively. The excellent reproducibility yielded a linear relationship (y = 15.41x - 7.983, R2 = 0.989) over the protein concentration range of 0.01 to 20 mg mL-1. Finally, AuNPs/CNC-assisted LDI-TOF MS provides clinically relevant fingerprint information of exosomal proteins in NSCLC serum, and characteristic proteins S100 calcium-binding protein A10, Urokinase plasminogen activator surface receptor, Plasma protease C1 inhibitor, Tyrosine-protein kinase Fgr and Mannose-binding lectin associated serine protease 2 represented excellent predictive biomarkers of NSCLC risk. A strategy to reduce AuNP cluster and protein aggregation in the sample using AuNPs/CNC, which improved the signal sensitivity and reproducibility of LDI-TOF MS analysis for intact proteins is introduced. Through AuNPs/CNC assisted LDI-TOF MS analysis, exosome protein fingerprint can effectively distinguished between healthy individuals and NSCLC patients. Moreover, five exosomal proteins represented excellent predictive biomarkers of NSCLC risk.image

Herein, we report the discovery of the catalytic asymmetric conjugated addition of allylstannanes to indol-2-ones promoted by Ni-(II)/chiral N,N'-dioxide. This method enables the stereodivergent construction of contiguous quaternary carbon centers (CQCCs), which can be readily achieved by a suitable combination of a chiral catalyst with stereospecific allylstannanes. This protocol allows for a unified access to all stereoisomers of 3,3-disubstituted oxindoles with CQCCs in good to excellent enantioselectivities and diastereoselectivities.

alpha-Aryl substituted nitroalkanes are valuable synthetic building blocks that can be easily converted into alpha-aryl substituted aldehydes, ketones, carboxylic acids, as well as amines. Herein, an efficient Cu/oxalamide-catalyzed coupling between nitroalkanes and (hetero)aryl halides (Br, I) was developed to direct access highly diverse alpha-aryl substituted nitroalkanes. Compared with the current state of art, this protocol is more environmentally friendly and practical for synthetic chemists. This approach is characterized by a broad substrate scope on both nitroalkane part (primary nitroalkanes and nitromethane) and sp(2) halide part ((hetero)aryl bromides/iodides and alkenyl bromides/iodides). The excellent functional group tolerance was observed, which would enable real world synthetic applications. More importantly, TON of current transformation reached to 3640, when some aryl iodides were used as coupling partners. This represents currently the highest catalyst turnover for transition-metal catalyzed alpha-arylation of nitroalkanes. Furthermore, the successful application in late-stage modification of complex molecules and synthesis of a known retinoid X receptor (RXR) antagonist exemplified its synthetic potential.

3,4-Syndiotactic polymerization of 1-(3-/4-methoxy-phenyl or 3,5-dimethoxy-phenyl)-1,3-butadienes (3-/4-MOPB or 3,5-DMOPB) and living copolymerization with 1-phenyl-1,3-butadiene (PB) can be successfully catalyzed by a series of CGC-type rare-earth metal dialkyl complexes at room temperature, affording 3,4-syndiotactic P-(3-/4-MOPB or 3,5-DMOPB)-s and random P-(3-/4-MOPB-co-PB)-s having 3-/4-MOPB contents in the range of 13-89 mol%. The research on the mechanism based on DFT suggests that the large steric hindrance around the metal center of the active species originated from the alternating coordination and insertion of MOPB monomers in two different empty coordination sites, respectively, in both cis-1,4-si- and cis-1,4-re-modes as well as the presence of the back-donation coordination of both the anti-eta 3-pi-allyl groups of the two last inserted MOPB units in the polymer chain might be the reason for complete 3,4-syndioselectivity. Significantly, the hydrogenated 3,4-syndiotactic P-(3-MOPB)-s and P-(3-MOPB-co-PB)-s exhibit self-healing properties, which is ascribed to the enhanced cohesive energy density and the removal of surface tensions by van der Waals forces through the dipole-dipole interactions of 3-position methoxy substituents of the pendent phenyl groups of adjacent polymer chains to form a lock key binding or interdigitated structure.

Due to their importance in natural products, organic synthesis, life science, and pharmaceuticals, reliable methods for the synthesis of chiral amines are urgently required. Here in this contribution, the dual chiral catalytic method has been established for the enantioselective reaction of terminal alkynes, aldehydes, and amines affording optically active propargylic amines with a decent enantioselectivity and a broad substrate scope. These propargylic amines have been demonstrated as platform molecules for the syntheses of different types of chiral amines. By applying this protocol, the asymmetric total syntheses of two linear monoamine natural products, (S)-5 and (S)-11, which were isolated from marine cyanobacteria Microcoleus lyngbyaceus, have been realized. The envisioned chiral ion pair, which has boosted the enantioselectivity greatly, and other key intermediates have been successfully characterized by MS studies.

While legacy fluorosurfactants have already been categorized as persistent organic pollutants, there appeared to be many strategies to develop alternatives. In this work, fluoroether double-chain phosphate surfactants (C72 diPAP-Na and C72 diPAP-NH4) were designed and synthesized with the initial intention of exploring the creation of new fluorosurfactants containing oxygen heteroatoms in the fluorocarbon chain segments to provide an alternative to the legacy long-chain fluorosurfactants. Furthermore, it was expected that they would even exceed the existing 6:2 fluorotelomer surfactants (6:2 diPAP-Na and 6:2 diPAP-NH4). Compared with characterizations of surface activity, foam performance, and wettability, the results showed that each of them has its own distinctive performance. Although the C72 series as new fluoroether surfactants cannot fully replace the 6:2 series of fluorosurfactants in terms of performance, there is a possibility of substitution in some aspects, which is of positive significance for further exploration to improve alternatives to legacy fluorosurfactants.

Chiral aliphatic amine compounds exhibit a range of physiological activities, making them highly sought-after in the pharmaceutical industry and biological research. One notable obstacle in studying these compounds stems from the pronounced steric hindrance surrounding the nitrogen atom. This characteristic often leads to a weak affinity of acyclic secondary amines for molecular probes, making their chiral discrimination intricate. In response to this challenge, our research has unveiled a novel F-19-labeled probe adept at recognizing and distinguishing between enantiomers of these acyclic secondary amines. By strategically incorporating a single fluorine atom as the F-19 label, we have managed to diminish the steric hindrance at the binding site. This alteration bolsters the probe's affinity toward bulkier analytes. As a testament to its effectiveness, we have successfully employed our probe in the chiral analysis of relevant pharmaceuticals, accurately determining their enantiocomposition.

A new, four component copper(I)-catalyzed interrupted click/radical relay cascade has been developed. This unprecedented interrupted click reaction provides a rapid modular synthesis of triazole sulfones, important privileged heterocyclic pharmacophores which cannot be accessed by a traditional click reaction. Radical interception of cupratetriazole, the key reaction intermediate formed in situ , is an important feature of this process.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

The metal-substituted silylenes are of high interest, as the theoretical studies indicated that the silylenes with electropositive substituents have a small Delta ES-T (singlet-triplet energy gap) or even the ground-state triplets. However, such compounds are highly unstable, and only two transient alkali metal-substituted silylenes M(tBu3Si)Si: (M = Li, K) were generated by photoextrusion of the alkali metal-substituted silacyclopropenes and merely studied by spectroscopic method (EPR) at low temperature (14 to 50 K). Herein, we report the generation of transient zinc-substituted silylenes from zinc silacyclopropanyl complexes under very mild and convenient conditions. The generated transient zinc-substituted silylenes are highly reactive and undergo intermolecular cycloaddition with alkenes for the synthesis of zinc-substituted Si-heterocyclic compounds. If there is no substrate, the zinc-substituted silylenes attack the C-C bonds of the beta-diketiminato ligands and break the C-C bonds. DFT studies further highlight the silylene nature of the zinc-substituted silylene and a very small Delta ES-T (4.4 kcal/mol).

Transcriptional dysregulation is a recurring pathogenic hallmark and an emerging therapeutic vulnerability in ovarian cancer. Here, we demonstrated that ovarian cancer exhibited a unique dependency on the regulatory machinery of transcriptional termination, particularly, cleavage and polyadenylation specificity factor (CPSF) complex. Genetic abrogation of multiple CPSF subunits substantially hampered neoplastic cell viability, and we presented evidence that their indispensable roles converged on the endonuclease CPSF3. Mechanistically, CPSF perturbation resulted in lengthened 3 ' -untranslated regions, diminished intronic polyadenylation and widespread transcriptional readthrough, and consequently suppressed oncogenic pathways. Furthermore, we reported the development of specific CPSF3 inhibitors building upon the benzoxaborole scaffold, which exerted potent antitumor activity. Notably, CPSF3 blockade effectively exacerbated genomic instability by down-regulating DNA damage repair genes and thus acted in synergy with poly(adenosine 5'-diphosphate-ribose) polymerase inhibition. These findings establish CPSF3-dependent transcriptional termination as an exploitable driving mechanism of ovarian cancer and provide a promising class of boron-containing compounds for targeting transcription-addicted human malignancies.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS auto immune diseases.

Nicotinamide adenine dinucleotide (NAD), a nucleotide-containing metabolite, can be incorporated into the RNA 50-terminus to result in NAD-capped RNA (NAD-RNA). Since NAD has been heightened as one of the most essential metabolites in cells, its linkage to RNA represents a critical but poorly studied modification at the epitranscriptomic level. Here, we design a highly sensitive method, DO-seq, to capture NAD-RNAs. Using Drosophila, we identify thousands of previously unexplored NAD-RNAs and their dynamics in the fly life cycle, from embryo to adult. We show the evidence that chromosomal clustering might be the structural basis by which co-expression can couple with NAD capping on physically and functionally linked genes. Furthermore, we note that NAD capping of cuticle genes inversely correlates with their gene expression. Combined, we propose NAD-RNA epitranscriptome as a hidden layer of regulation that underlies biological processes. DO-seq empowers the identification of NAD-capped RNAs, facilitating functional investigation into this modification.

NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N- terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid -like condensates driven by their N- terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.

An iodine radical mediated cascade [3 + 2] carbocyclization of ene-vinylidenecyclopropanes with thiols and selenols via photoredox catalysis has been reported in this paper. With this visible light-induced photocatalytic protocol, an efficient synthetic methodology for the rapid construction of sulfur- and selenium-containing polycyclic derivatives in moderate to good yields has been realized with broad substrate scope. Mechanistic investigations were also performed using control experiments, deuterium labeling and Stern-Volmer analysis as well as DFT calculations, suggesting that this cascade cyclization reaction stems from an iodine radical addition to the allenyl moiety of ene-vinylidenecyclopropane along with a cascade cyclization. Then, the reaction proceeds through a cyclopropane-ring opening pathway along with a HAT process and an intramolecular substitution. Further transformation of the obtained product has also been disclosed.