The invention of a well-defined Cu(III) fluoride complex Me4N+[Cu(CF3)(3)(F)](-) 1 enabled to access a versatile of functionalized Cu(III) complexes [Me4N](+)[Cu(X)(CF3)(3)](-) (X = C6F5, C6F5C C, CN, Cl, N-3, (BuOO)-Bu-t, SCN, OAc, SAr), many of them for the first time. The availability of these complexes allowed us to evaluate the trans-influence order of ligand in Cu(III) complexes: Bn > CF3- > C6F5- > N-3(-) > py similar to CH3- similar to C6F5C C > NO2PhO- similar to (BuOO-)-Bu-t similar to CH3COO- > F-.

Blue afterglow constitutes of one of the primary afterglow colors and can convert into other afterglow colors through energy transfer. The reported studies show the fabrication of blue afterglow emitters, but most of them are formed by room-temperature phosphorescence mechanism and require UVB lights as excitation source (these high-energy lights may damage organic systems). Here we report visible-light-excitable blue thermally activated delayed fluorescence type (TADF-type) afterglow materials via delicate control of excited states in difluoroboron beta-diketonate (BF2bdk) systems. Tiny change of the substituents in BF2bdk system has been found to pose significant influence on excited state energy levels and consequently narrow the singlet-triplet splitting energy of the system. As a result, both forward and reverse intersystem crossing have been accelerated, leading to the emergence of BF2bdk's TADF-type organic afterglow in rigid crystalline matrices. The resultant TADF-type afterglow materials exhibit emission lifetimes of several hundred milliseconds, photoluminescence quantum yield (PLQY) of 24.7 % and display temperature responsive property. In contrast to blue room-temperature phosphorescence materials that require UVB excitation, this study reports visible-light-excitable blue TADF-type afterglow materials via delicate control of excited states in difluoroboron beta-diketonate systems. image

Composite materials have significantly advanced with the integration of inorganic nanoparticles as fillers in polymers. Achieving fine dispersion of these nanoparticles within the composites, however, remains a challenge. This study presents a novel solution inspired by the natural structure of Xanthium. We have developed a polymer of intrinsic microporosity (PIM)-based porous coupling agent, named PCA. PCA's rigid backbone structure enhances interfacial interactions through a unique intermolecular interlocking mechanism. This approach notably improves the dispersion of SiO2 nanoparticles in various organic solvents and low-polarity polymers. Significantly, PCA-modified SiO2 nanoparticles embedded in polyisoprene rubber showed enhanced mechanical properties. The Young's modulus increases to 30.7 MPa, compared to 5.4 MPa in hexadecyltrimethoxysilane-modified nanoparticles. Further analysis shows that PCA-modified composites not only become stiffer but also gain strength and ductility. This research demonstrates a novel biomimetic strategy for enhancing interfacial interactions in composites, potentially leading to stronger, more versatile composite materials.

Free unsaturated fatty acids (UFA) are key intermediates of lipid metabolism and participate in many metabolic pathways with specific biological functions. Although various fragmentation-based methods for pinpointing C=C locations in UFA were developed, the current mass spectrometry methods are difficult to simultaneously differentiate geometric isomers and positional isomers in trace samples due to low ionization efficiency, low conversion, and low resolution. Herein, an intramolecular ring-chain equilibrium elimination strategy via 4-plex stable isotope labeling dual derivatization-assisted ion mobility-mass spectrometry was developed, thereby one-pot specifically labeling C=C and carboxyl groups among the trace and unstable UFA with high sensitivity, high efficiency, and good substrate generality. It achieved fast separation of both C=C positional and geometric isomers with high resolution, which benefited from eliminating the intramolecular ring-chain equilibrium by suppressing the formation of salt bridges between free carboxyl groups and pyridine cations. 4-plex stable isotope labeling reagents showed similar reactivity, enabling high-throughput quantitative analysis of omics. This method was successfully applied for accurate and rapid identification of the UFA composition in olive oil extract. These results suggest that the developed method provides new insight for rapid characterization of UFA C=C positional and geometric isomers in complex samples to explore disease biomarkers and food quality control indicators.

Creating different pore environments within a covalent organic framework (COF) will lead to useful multicompartment structure and multiple functions, which however has been scarcely achieved. Herein we report designed synthesis of three two-dimensional COFs with amphiphilic porosity by steric-hindrance-mediated precision hydrophilic-hydrophobic microphase separation. Dictated by the different steric effect of the substituents introduced to a monomer, dual-pore COFs with kgm net, in which all hydroxyls locate in trigonal micropores while hydrophobic sidechains exclusively distribute in hexagonal mesopores, have been constructed to form completely separated hydrophilic and hydrophobic nanochannels. The unique amphiphilic channels in the COFs enable the formation of Janus membranes via interface growth. This work has realized the creation of two types of channels with opposite properties in one COF, demonstrating the feasibility of introducing different properties/functions into different pores of heteropore COFs, which can be a useful strategy to develop multifunctional materials. Creating different pore environments within a covalent organic framework (COF) leads to useful multicompartment structure and multiple functions. Here, the authors propose a strategy to construct amphiphilic COFs with separated hydrophilic and hydrophobic nanochannels by precisely controlling the distribution of hydrophilic and hydrophobic segments in two different kinds of pores.

Epoxides are important synthetic intermediates due to their high propensity to undergo ring-opening to give a variety of products with useful functional groups. In this study, we disclose a non-halide-mediated electrochemical epoxidation of alkenes to form epoxides using water as an oxygen source. This method catalyzed by (TMP)MnCl (TMP = tetramesitylporphyrin) exhibits remarkable efficiency, enabling the epoxidation of both aromatic and aliphatic alkenes with excellent faradaic efficiencies (up to 89%). Preliminary mechanistic studies suggest the MnV 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 O species generated from single electron oxidations serves as the key intermediate for the epoxidation reaction. An efficient electrochemical epoxidation of alkenes catalyzed by (TMP)MnCl with water as the oxygen source is disclosed. The reaction achieved impressive faradaic efficiencies (up to 89%) for a broad range of substrates.

Cypemycin is a parent linaridin peptide known to contain nonproteinogenic dehydrobutyrine, N,N-dimethylalanine, and aminovinyl-cysteine residues. The enzymatic process by which this ribosomally synthesized peptide is formed remains elusive largely because of the deficiency of knowledge in post-translational modifications (PTMs) conducted by CypH and CypL, the two membrane-associated enzymes unique to linaridin biosynthesis. Based on heterologous reconstitution of the pathway in Streptomyces coelicolor, we report the detailed structural characterization of cypemycin as a previously unknown, D-amino acid-rich linaridin. In particular, the unprecedented family-determining activity of CypH and CypL was revealed, which, in addition to hydrolysis for removal of the N-terminal leader peptide, leads to transformation of the core peptide part of the precursor peptide through mechanistically related 16 reactions for residue epimerization (11 amino acids), dehydration (4 Thr), and dethiolation (Cys19). Subsequent functionalization for linaridin maturation includes CypD-involved aminovinyl-cysteine formation and N,N-dimethylation of the newly exposed N-terminal D-Ala residue that requires CypM activity. Genetic, chemical, biochemical, engineering, and modeling approaches were used to access the structure of cypemycin and the versatility of the CypH and CypL combination that is achieved in catalysis. This work furthers the appreciation of PTM chemistry and facilitates efforts for expanding linaridin structural diversity using synthetic biology methods.

Plasma membrane heterogeneity is a key biophysical regulatory principle of membrane protein dynamics, which further influences downstream signal transduction. Although extensive biophysical and cell biology studies have proven membrane heterogeneity is essential to cell fate, the direct link between membrane heterogeneity regulation to cellular function remains unclear. Heterogeneous structures on plasma membranes, such as lipid rafts, are transiently assembled, thus hard to study via regular techniques. Indeed, it is nearly impossible to perturb membrane heterogeneity without changing plasma membrane compositions. In this study, we developed a high- spatial resolved DNA- origami -based nanoheater system with specific lipid heterogeneity targeting to manipulate the local lipid environmental temperature under near- infrared (NIR) laser illumination. Our results showed that the targeted heating of the local lipid environ-ment influences the membrane thermodynamic properties, which further triggers an integrin- associated cell migration change. Therefore, the nanoheater system was further applied as an optimized therapeutic agent for wound healing. Our strategy provides a powerful tool to dynamically manipulate membrane heterogeneity and has the potential to explore cellular function through changes in plasma membrane biophysical properties.

Kasha's exciton model proposes that T-1 energy levels of organic compounds are insensitive to molecular aggregation and microenvironment change because of negligible small transition dipole moments of T-1 states. This model holds true in most organic systems till now. Here we report the fabrication of twisted organic phosphors with intramolecular charge transfer characters and flexible molecular structures. When doped into different organic matrices, the twisted phosphor adopts different conformation, exhibits distinct phosphorescence colors and T-1 energy levels, which violates Kasha's exciton model in organic system. Given that the change of phosphorescence colors and maxima can be readily distinguished by human eyes and conventional instrument, the twisted phosphors would be exploited as a new type of molecular probe, which would exhibit potential application in optical sensing and stimuli-responsive systems.

Ketamine was thought to induce rapid antidepressant responses by inhibiting GluN2B-containing N-methyl-d-aspartic acid (NMDA) receptors (NMDARs), which presents a promising opportunity to develop better antidepressants. However, adverse side effects limit the broader application of ketamine and GluN2B inhibitors are yet to be approved for clinical use. It is unclear whether ketamine acts solely through GluN2B-dependent mechanisms. The present study reports that the loss of another major NMDAR subunit, GluN2A, in adult mouse brains elicits robust antidepressant-like responses with limited impact on the behaviors that mimic the psychomimetic effects of ketamine. The antidepressant-like behavioral effects of broad NMDAR channel blockers, such as ketamine and MK-801 (dizocilpine), were mediated by the suppression of GluN2A, but not by the inhibition of GluN2B. Moreover, treatment with ketamine or MK-801 rapidly increased the intrinsic excitability of hippocampal principal neurons through GluN2A, but not GluN2B. Together, these findings indicate that GluN2A mediates ketamine-triggered rapid antidepressant-like responses. Su et al. show that loss of GluN2A in adult mice is sufficient to elicit antidepressant-like responses without evoking psychomimetic effects, and that GluN2A is necessary for ketamine and MK-801 to induce rapid antidepressant-like effects.

A convergent synthesis of the dodecasaccharide scaffold of axinelloside A was achieved through Au(I)-catalyzed [6+6] glycosylation. The initially devised [3+1+2] assembly of the nonreducing hexasaccharide fragment was low-yielding, whereas a convergent [3+3] glycosylation under Au(I) catalysis was proven feasible, allowing for a semi-gram scale preparation of the wanted hexasaccharide. The requisite 1,2-cis glycosidic bonds were forged in a highly stereoselective fashion by virtue of remote acetyl group participation, and judicious manipulation of protecting groups. The synthetic dodecasaccharide has been properly protected for the downstream elaboration toward its natural form. A convergent synthesis of properly protected dodecasaccharide backbone of axinelloside A was accomplished by virtue of an Au(I)-catalyzed [6+6] glycosylation. The 1,2-cis configuration of the glycosidic bonds was well controlled by judicious choice of protecting groups as well as promotion conditions.+ image

Due to its unique electronic properties, the difluoromethylene group (CF2) has served as a valuable unity in the design of biologically active molecules. Since gamma-lactones display a broad range of biological properties, alpha,alpha-difluoro-gamma-lactones may exhibit unexpected biological activities, and thus their synthesis has received increasing attention. Traditional synthetic methods suffer from tedious multi- step processes, and very few effective methods have been reported recently. Herein, we describe the difunctionalization of alkenes with BrCF2CO2K under photoredox catalysis with the use of a boron-Lewis acid for the access to alpha,alpha-difluoro-gamma-lactones. In this transformation, the alkene substrates and the used reagents, including BrCF2CO2K and the boron-Lewis acid, PhB(OH)(2) or BF3 center dot THF, are cheap and widely available. High efficiency and atom economy may make this protocol attractive.

Plasma membrane heterogeneity is a key biophysical regulatory principle of membrane protein dynamics, which further influences downstream signal transduction. Although extensive biophysical and cell biology studies have proven membrane heterogeneity is essential to cell fate, the direct link between membrane heterogeneity regulation to cellular function remains unclear. Heterogeneous structures on plasma membranes, such as lipid rafts, are transiently assembled, thus hard to study via regular techniques. Indeed, it is nearly impossible to perturb membrane heterogeneity without changing plasma membrane compositions. In this study, we developed a high- spatial resolved DNA- origami -based nanoheater system with specific lipid heterogeneity targeting to manipulate the local lipid environmental temperature under near- infrared (NIR) laser illumination. Our results showed that the targeted heating of the local lipid environ-ment influences the membrane thermodynamic properties, which further triggers an integrin- associated cell migration change. Therefore, the nanoheater system was further applied as an optimized therapeutic agent for wound healing. Our strategy provides a powerful tool to dynamically manipulate membrane heterogeneity and has the potential to explore cellular function through changes in plasma membrane biophysical properties.

A new difluoroalkylation reagent Sulfox-CF2SO2Ph bearing both sulfoximine and sulfone moieties was prepared from commercially available SulfoxFluor and PhSO2CF2H. On one hand, the Sulfox-CF2SO2Ph reagent could act as a (phenylsulfonyl)difluoromethyl radical source under photoredox catalysis, in which the arylsulfoximidoyl group is selectively removed. On the other hand, under basic conditions, Sulfox-CF2SO2Ph could serve as a difluorocarbene precursor for S- and O-difluoromethylations with S- and O-nucleophiles, respectively, in which the phenylsulfonyl group in Sulfox-CF2SO2Ph is selectively removed (followed by alpha-elimination of the arylsulfoximidoyl group).

alpha-Cyanophosphonates, which are useful reagents for the Horner-Wittig reaction, were synthesized under solvent-free conditions by using a choline chloride-zinc chloride deep-eutectic solvent (DES) as a catalyst. This is only the second report on the synthesis of these compounds. In the previous report, diethyl trimethylsilyl phosphite was used as a reagent and TiCl4 as a catalyst, whereas in this study, both the reagent (triphenylphosphine) and the catalyst (choline chloride-zinc chloride DES) are cheaper, more readily available, and less harmful than those used in the previous work. Moreover, the process involves an interesting cascade reaction between a beta-nitrostyrene and two equivalents of triphenyl phosphite, leading to the desired product by a new synthetic route. The products can be used in the pharmaceutical and agricultural industries, in addition to their synthetic applications in the preparation of alpha,beta-unsaturated nitriles. The reactions were completed on using 20 mol% of DES at 80 degrees C in six hours. Ten different beta-nitrostyrenes were synthesized in yields of 55-87% after purification. beta-Nitrostyrenes containing electron-donating groups showed higher yields. The reaction failed when aliphatic or heteroaromatic nitroalkenes or beta-nitrostyrenes with electron-withdrawing substituents were employed. Finally, three plausible mechanistic routes are proposed for the reaction, starting with the nucleophilic addition of triphenyl phosphite to the carbon, nitrogen, or oxygen atom in the alpha-position.

The first stereodivergent umpolung 1,5-conjugate addition reaction via synergistic Pd/Cu catalysts is reported. By dictating the absolute configuration of each chiral ligand ligated to corresponding metals, all four stereoisomers of the products are easily achieved. A series of amino acid moieties are introduced to the gamma-position of the conjugated esters in high yields with excellent diastereoselectivities and enantioselectivities. The downstream transformations highlight the synthetic value of the method.

Catalytic asymmetric carboxylation of readily available alkenes with CO2, an abundant and sustainable one-carbon building block, that gives access to value-added alpha-stereogenic carboxylic acids in an atom- and step-economic manner is highly attractive. However, it has remained a formidable challenge for the synthetic community. Here, the first example of Cu-catalyzed highly regio- and enantioselective boracarboxylation reaction on various arylalkenes with diboron under an atmospheric pressure of CO(2 )is described, which afforded a variety of chiral beta-boron-functionalized alpha-aryl carboxylic acids with up to 87% yield and 97% ee under mild conditions. Importantly, alpha-substituted arylalkenes could also be subject to this protocol with excellent enantiopurities, thereby rendering an efficient approach for the generation of enantioenriched carboxylic acids with an alpha-chiral all-carbon quaternary center. Moreover, high functional group tolerance, scalable synthesis, and facile access to bioactive compounds, like (-)-scopolamine, (-)-anisodamine, and (-)-tropicamide, further demonstrated the synthetic utility of this strategy.

Ph3P+CF2CO2- (PDFA), a reagent that was developed by us recently, has found widespread applications in the synthesis of fluorinated molecules. Its great synthetic potential stimulates us to develop an effective synthetic route on a kilogram scale, which is described in this work. The used reagents are all cheap and easily available. We also demonstrate that the aldehyde group is significantly more reactive than the double bond group toward PDFA even though both of these two groups are very reactive toward PDFA.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)(2), as the catalytically active intermediate, which can decay to a dimeric species (kappa(3)-PCNOx)IrH(mu-H)(2)IrH(kappa(2)-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H-2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

The conventional N-glycosylation methods for nucleoside synthesis usually require strongly acidic or basic conditions. Here we report the decarboxylative C(sp(3))-N coupling of glycosyl N-hydroxyphthalimide esters with nucleobases via dual photoredox/Cu catalysis, which offered a mild approach to nucleoside analogues. A total synthesis of oxetanocin A, an antiviral natural product containing an oxetanose moiety, has been achieved by using this method.

1,4-Enyne units are ubiquitous skeletons in biologically active molecules and natural products. Especially, they represent versatile building blocks for abundant downstream derivatizations via controllable modifications of both alkene and alkyne units independently. Recently, great efforts have been made to establish efficient protocols to achieve optically active 1,4-enynes. Considering the enormous application potential of enantioenriched 1,4-enyne units but no related review on this topic has been described, here we aim to provide a comprehensive summary on the catalytic methods established for enantioselective constructions of these intriguing skeletons. According to the reaction types, this review is divided into five parts, including asymmetric allylic substitution, asymmetric propargylic substitution, asymmetric alkynylallylic substitution, asymmetric hydroalkynylation and asymmetric 1,2-addition of alkynes to conjugated imines or ketones. (c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Herein, a concise, effective, and scalable strategy is reported that the introduction of polar molecules (PMs) (e.g., anisole (PhOMe), phenetole (PhOEt), 2-methoxynaphthalene (NaphOMe), thioanisole (PhSMe), and N,N-dimethylaniline (PhNMe2)) as continuously coordinated neutral ligand of cationic active species in situ generated from the constrain-geometry-configuration-type rare-earth metal complexes A-F/AliBu3/[Ph3C][B(C6F5)4] ternary systems can easily switch the regio- and stereoselectivity of the polymerization of conjugated dienes (CDs, including 2-subsituted CDs such as isoprene (IP) and myrcene (MY), 1,2-disubstituted CD ocimene (OC), and 1-substituted polar CD 1-(para-methoxyphenyl)-1,3-butadiene (p-MOPB)) from poor selectivities to high selectivities (for IP and MY: 3,4-selectivity up to 99%; for OC: trans-1,2-selectivity up to 93% (mm up to 90%); for p-MOPB: 3,4-syndioselectivity (3,4- up to 99%, rrrr up to 96%)). DFT calculations explain the continuous coordination roles of PMs on the regulation of the regio- and stereoselectivity of the polymerization of CDs. In comparison with the traditional strategies, this strategy by adding some common PMs is easier and more convenient, decreasing the synthetic cost and complex operation of new metal catalyst and cocatalyst. Such regio- and stereoselective regulation method by using PMs is not reported for the coordination polymerization of olefins catalyzed by rare-earth metal and early transition metal complexes. The introduction of polar molecules (PMs) (e.g., PhOMe, PhOEt, NaphOMe, PhSMe, and PhNMe2) to the CGC-type rare-earth metal complexes A-F/AliBu3/[Ph3C][B(C6F5)4] ternary catalytic systems can easily switch the regio- and stereoselectivity of the polymerization of conjugated dienes (CDs) (e.g., IP, MY, OC, and p-MOPB) from poor selectivities to high selectivities. image

Ph3P+CF2CO2- (PDFA), a reagent that was developed by us recently, has found widespread applications in the synthesis of fluorinated molecules. Its great synthetic potential stimulates us to develop an effective synthetic route on a kilogram scale, which is described in this work. The used reagents are all cheap and easily available. We also demonstrate that the aldehyde group is significantly more reactive than the double bond group toward PDFA even though both of these two groups are very reactive toward PDFA.

As an interim paradigm for the catalysts between those based on more conventional mononuclear molecular Pd complexes and Pd-n nanoparticles widely used in organic synthesis, polynuclear palladium clusters have attracted great attention for their unique reactivity and electronic properties. However, the development of Pd cluster catalysts for organic transformations and mechanistic investigations is still largely unexploited. Herein, we disclose the use of trinuclear palladium (Pd3Cl) species as an active catalyst for the direct C-H alpha-arylation of benzo[b]furans with aryl iodides to afford 2-arylbenzofurans in good yields under mild conditions. With this method, broad substrate adaptability was observed, and several drug intermediates were synthesized in high yields. Mechanistic studies indicated that the Pd-3 core most likely remained intact throughout the reaction course.

Rationale: Diaryliodonium salts are useful electrophilic reagents in organic chemistry, finding extensive applications in arylations and photo-induced polymerizations. However, comprehensive mechanistic investigations, particularly concerning the mass spectrometric behaviors of diaryliodonium salts, are relatively scarce in the literature. Methods: Diaryliodonium salts could be readily ionized using electrospray ionization mass spectrometry (ESI-MS) to give [Ar-1-I+-Ar-2], and high-resolution ESI-tandem mass spectrometry (MS/MS) experiments were conducted to investigate their gas-phase chemical reactions. Results: Investigations on ESI-MS/MS of [Ar-1-I+-Ar-2] revealed two major fragmentation patterns: (1) reductive elimination resulting in the diaryl coupling product ion [Ar-1-Ar-2](+center dot) by the loss of I; (2) generation of aryl cations [Ar-1](+) or [Ar-2](+) through cleavage of the C-I bonds. We revealed that the introduction of NO2 into Ar-2 of [Ar-1-I+-Ar-2] could lead to an unexpected fragmentation ion [(ArO)-O-1](+) in MS/MS, arising from an O-atom transfer process from NO2 to Ar-1. Particularly, when NO2 was ortho-positioned to the iodine in Ar-2, the [(ArO)-O-1](+) sometimes exhibited dominant behavior. Conclusions: Comprehensive ESI-MS/MS studies and theoretical calculations provided strong support for the O-atom transfer mechanistic pathway: [Ar-1-I+-(o-NO2-Ar-2)] initially underwent a Smiles rearrangement to the intermediate [Ar-1-O-(o-NO-(ArI)-I-2)](+), which subsequently dissociated to [(ArO)-O-1](+) or [o-NO-(ArI)-I-2](+center dot). Herein, we proposed an unexpected ortho effect in the gas-phase fragmentation reaction of [Ar-1-I+-(o-NO2-Ar-2)], in which the crucial determinant factor for the aryl migration was identified as the Smiles rearrangement reaction.

Light provides high temporal precision for neuronal modulations. Small molecules are advantageous for neuronal modulation due to their structural diversity, allowing them to suit versatile targets. However, current optochemical methods release uncaged small molecules with uniform concentrations in the irradiation area, which lack spatial specificity as counterpart optogenetic methods from genetic encoding for photosensitive proteins. Photocatalysis provides spatial specificity by generating reactive species in the proximity of photocatalysts. However, current photocatalytic methods use antibody-tagged heavy-metal photocatalysts for spatial specificity, which are unsuitable for neuronal applications. Here, we report a genetically encoded metal-free photocatalysis method for the optochemical modulation of neurons via deboronative hydroxylation. The genetically encoded photocatalysts generate doxorubicin, a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted drug delivery are achieved by this method. The distinct signaling pathway dissection in a single projection is enabled by the dual optogenetic and optochemical control of synaptic transmission. The itching signaling pathway is investigated by photocatalytic uncaging under live-mice skin for the first time by visible light irradiation. The cell-type-specific release of baclofen reveals the GABA(B)R activation on Na(V)1.8-expressing nociceptor terminals instead of pan peripheral sensory neurons for itch alleviation in live mice.

Ph3P+CF2CO2- (PDFA), a reagent that was developed by us recently, has found widespread applications in the synthesis of fluorinated molecules. Its great synthetic potential stimulates us to develop an effective synthetic route on a kilogram scale, which is described in this work. The used reagents are all cheap and easily available. We also demonstrate that the aldehyde group is significantly more reactive than the double bond group toward PDFA even though both of these two groups are very reactive toward PDFA.

BackgroundWith the rapidly increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), neuronal complications associated with these diseases have resulted in significant burdens on healthcare systems. Meanwhile, effective therapies have remained insufficient. A novel fatty acid called S-9-PAHSA has been reported to provide metabolic benefits in T2DM by regulating glucose metabolism. However, whether S-9-PAHSA has a neuroprotective effect in mouse models of T2DM remains unclear.MethodsThis in vivo study in mice fed a high-fat diet (HFD) for 5 months used fasting blood glucose, glucose tolerance, and insulin tolerance tests to examine the effect of S-9-PAHSA on glucose metabolism. The Morris water maze test was also used to assess the impact of S-9-PAHSA on cognition in the mice, while the neuroprotective effect of S-9-PAHSA was evaluated by measuring the expression of proteins related to apoptosis and oxidative stress. In addition, an in vitro study in PC12 cells assessed apoptosis, oxidative stress, and mitochondrial membrane potential with or without CAIII knockdown to determine the role of CAIII in the neuroprotective effect of S-9-PAHSA.ResultsS-9-PAHSA reduced fasting blood glucose levels significantly, increased insulin sensitivity in the HFD mice and also suppressed apoptosis and oxidative stress in the cortex of the mice and PC12 cells in a diabetic setting. By suppressing oxidative stress and apoptosis, S-9-PAHSA protected both neuronal cells and microvascular endothelial cells in in vivo and in vitro diabetic environments. Interestingly, this protective effect of S-9-PAHSA was reduced significantly when CAIII was knocked down in the PC12 cells, suggesting that CAIII has a major role in the neuroprotective effect of S-9-PAHSA. However, overexpression of CAIII did not significantly enhance the protective effect of S-9-PAHSA.ConclusionS-9-PAHSA mediated by CAIII has the potential to exert a neuroprotective effect by suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, S-9-PAHSA has the capability to reduce fasting blood glucose and LDL levels and enhance insulin sensitivity in mice fed with HFD. S-9-PAHSA has the potential to exert neuroprotective effects mediated by CAIII via suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, it has the capability to reduce fasting blood glucose and LDL and enhance insulin sensitivity in mice with a high-fat diet.image

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure -guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).