Chiral-Boron Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of 2'-Hydroxychalcones with N-2,2,2-Trifluoroethylisatin Ketimines.

A highly efficient asymmetric [3 + 2] cycloaddition reaction of 2'-hydroxychalcones with N-2,2,2-trifluoroethylisatin ketimines catalyzed by a (R)-3,3'-I2-BINOL-boron complex was developed. A broad range of 3,2'-pyrrolidinyl spirooxindole derivatives bearing a CF3-substituted pyrrolidine moiety with four contiguous stereocenters was prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and excellent stereocontrol.

Brozopine ameliorates cognitive impairment via upregulating Nrf2, antioxidation and anti-inflammation activities.

Oxidative stress and inflammation are crucial factors contributing to the occurrence and development of vascular dementia (VD). In a previous study, we demonstrated that brozopine (BZP) is an anti-ischemic drug. In this study, a model of VD in rats with modified permanent bilateral common carotid artery occlusion (2-VO) was established in vivo, a model of cellular excitotoxicity/oxidative stress was established via L-glutamate-induced PC12 cell injury, a model of neuroinflammation was established in LPS-induced BV2 cells in vitro, and the ameliorative effect of BZP on cognitive impairment was assessed. BZP treatment improved memory deficit in VD rats through inhibiting Ca2+overload and the levels of oxidative stress, ferroptosis, and inflammatory markers (IL-1ß, IL-6, and COX-2) in different brain regions. Additionally, we found that the levels of inflammatory markers in the plasma were also reduced in the VD rats. BZP was further found to have antioxidative stress, antiferroptosis (ferroptosis markers: GPX4, P53, and ACSL4), and antineuroinflammatory effects in PC12 and BV2 cells. Its mechanisms of action were found to be related to the activation of the Nrf2/TLR4/NF-κB pathway; the protective effect of BZP was partially inhibited after using Nrf2-specific inhibitors. Thus, BZP has therapeutic properties for the potential mitigation of cognitive impairment.

Nickel-catalyzed regiodivergent hydrosilylation of α-(fluoroalkyl)styrenes without defluorination.

The fluoroalkyl-containing organic molecules are widely used in drug discovery and material science. Herein, we report ligand regulated nickel(0)-catalyzed regiodivergent hydrosilylation of α-(fluoroalkyl)styrenes without defluorination, providing an atom- and step-economical synthesis route of two types of fluoroalkyl substituted silanes with exclusive regioselectivity. The anti-Markovnikov addition products (ß-fluoroalkyl substituted silanes) are formed with monodentate phosphine ligand. Noteworthy, the bidentate phosphine ligand promote the generation of the more challenging Markovnikov products (α-fluoroalkyl substituted silanes) with tetrasubstituted saturated carbon centers. This protocol features with easy available starting materials and commercially available nickel catalysis, a wide range of substrates and excellent regioselectivity. The structure divergent products undergo a variety of transformations. Comprehensive mechanistic studies including the inverse kinetic isotope effects demonstrate the regioselectivity controlled by ligand structure through α-CF3 nickel intermediate. DFT calculations reveal a distinctive mechanism involving an open-shell singlet state, which is crucial for generating intricate tetra-substituted Markovnikov products.

Brønsted acid catalyzed Ficini [2 + 2] cycloaddition of ynamides with enones.

Herein, we describe a novel metal-free Brønsted acid-catalyzed Ficini [2 + 2] cycloaddition of ynamides with enones under mild reaction conditions, leading to the formation of various cyclobutenamides in generally good to excellent yields within short reaction times. This work represents the first example of ynamides involved in a nonmetal-catalyzed [2 + 2] cycloaddition with enones.

Synthesis of Sterically Hindered Dialkyl Ethers via Palladium-Catalyzed Fluoro-alkoxylation of gem-Difluoroalkenes.

Organofluorine compounds are of high value in medicinal and agricultural chemistry. Herein, we report a palladium-catalyzed fluoro-alkoxylation of gem-difluoroalkenes for the synthesis of much more challenging sterically hindered ethers. This reaction represents a direct synthesis method for α-trifluoromethyl ethers with a broad functional group tolerance and excellent regioselectivity. This system employs N-fluorobenzenesulfonimide (NFSI) as an electrophilic fluorine source and alcohols as nucleophilic donors, including but not limited to sterically hindered tert-substituted alcohols.

In situ autophagy regulation in synergy with phototherapy for breast cancer treatment.

Autophagy is an important factor in reducing the efficacy of tumor phototherapy (including PTT and PDT). Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT. This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy. To achieve this goal, we first synthesized TRANSFERRIN (Tf) biomimetic mineralized nano-tellurium (Tf-Te) as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly. The autophagy inhibitor hydroxychloroquine (HCQ) and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ. After entering breast cancer cells through the "self-guidance system", Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation, to efficiently induce PTT/PDT effect. Meanwhile, the disulfide bond broke down in response to GSH, and the nanoparticles disintegrated to release Fe2+ and HCQ at fixed points. They simultaneously induce lysosomal alkalinization and increased osmotic pressure, effectively inhibit autophagy, and synergistically enhance the therapeutic effect of phototherapy. In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6% on 4T1 tumor-bearing mice. This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

TMSOTf-Catalyzed [4 + 2] Annulation of Ynamides and ß-(2-Aminophenyl)-α,ß-ynones for the Synthesis 2-Aminoquinolines.

A metal-free TMSOTf-catalyzed [4 + 2] annulation of ynamides with ß-(2-aminophenyl)-α,ß-ynones enables the regiospecific and facile assembly of 2-aminoquinoline frameworks. The catalyst TMSOTf presented a remarkable advancement compared to previously reported transition-metal catalysts. A wide range of 3-aryl/alkyl-substituted 2-aminoquinolines were generated in moderate to excellent yields due to the mild conditions.

Umpolung reactivity of strained C-C σ-bonds without transition-metal catalysis.

Umpolung is an old and important concept in organic chemistry, which significantly expands the chemical space and provides unique structures. While, previous research focused on carbonyls or imine derivatives, the umpolung reactivity of polarized C-C σ-bonds still needs to explore. Herein, we report an umpolung reaction of bicyclo[1.1.0]butanes (BCBs) with electron-deficient alkenes to construct the C(sp3)-C(sp3) bond at the electrophilic position of C-C σ-bonds in BCBs without any transition-metal catalysis. Specifically, this transformation relies on the strain-release driven bridging σ-bonds in bicyclo[1.1.0]butanes (BCBs), which are emerged as ene components, providing an efficient and straightforward synthesis route of various functionalized cyclobutenes and conjugated dienes, respectively. The synthetic utilities of this protocol are performed by several transformations. Preliminary mechanistic studies including density functional theory (DFT) calculation support the concerted Alder-ene type process of C-C σ-bond cleavage with hydrogen transfer. This work extends the umpolung reaction to C-C σ-bonds and provides high-value structural motifs.

Redox-Regulated Synthetic Channels: Enabling Reversible Ion Transport by Modulating the Ion-Permeation Pathway.

Natural redox-regulated channel proteins often utilize disulfide bonds as redox sensors for adaptive regulation of channel conformations in response to diverse physiological environments. In this study, we developed novel synthetic ion channels capable of reversibly switching their ion-transport capabilities by incorporating multiple disulfide bonds into artificial systems. X-ray structural analysis and electrophysiological experiments demonstrated that these disulfide-bridged molecules possess well-defined tubular cavities and can be efficiently inserted into lipid bilayers to form artificial ion channels. More importantly, the disulfide bonds in these molecules serve as redox-tunable switches to regulate the formation and disruption of ion-permeation pathways, thereby achieving a transition in the transmembrane transport process between the ON and OFF states.

Iodine-Mediated δ-Amination of sp3 C-H Bonds.

We present a direct δ-amination reaction of sp3 C-H bonds, employing molecular iodine (I2) as the sole oxidant under transition-metal-free conditions. This remote C-H functionalization approach is operationally simple and provides facile, efficient access to pyrrolidines and related heterocyclic derivatives from readily accessible substrates.

Synthesis of 2,2-difunctionalized 2H-azirines via I2-mediated annulation of enamines.

Various 2,2-difunctionalized 2H-azirines were synthesized via I2-mediated annulation reactions of readily accessible enamines in the presence of nitrogen or non-nitrogen nucleophiles. The features of the present synthesis process also include no use of transition metals, simple operation, mild reaction conditions, a broad substrate scope, and gram-scale synthesis.

The novel selective TLR7 agonist GY101 suppresses colon cancer growth by stimulating immune cells.

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells. Herein, we identified a novel selective TLR7 agonist, GY101, and determined its ability to activate TLR7. In summary, in vitro, compound GY101 significantly induced the secretion of IL-6, IL-12, TNF-α and IFN-γ in mouse splenic lymphocytes; in vivo, peritumoral injection of GY101 significantly suppressed colon cancer CT26, as well as poorly immunogenic B16-F10 and 4T1 cancer cell-derived tumor growth by activating the infiltration of lymphocytes and polarization of M2-like macrophages into M1-like macrophages. These results demonstrate that GY101, as a potent TLR7 agonist, holds great potential for cancer immunotherapy.

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants.

This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC50 > 100 µM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.

Annulations of Ynamides with 1,2-Benzisothiazoles to Construct 1,4-Benzothiazepines and 3-Aminoisoquinolines.

Two distinct TMSOTf-catalyzed annulation reactions between ynamides and 1,2-benzisothiazoles have been developed. The direction of the reaction could be easily switched by applying different thermodynamic-controlled conditions. At room temperature, ynamides undergo a [5 + 2] annulation reaction with 1,2-benzisothiazoles to afford 1,4-benzothiazepines, whereas under heating conditions a desulfurizative annulation reaction proceeds well to access 3-aminoisoquinolines. These two protocols provide biologically important 1,4-benzothiazepines and 3-aminoisoquinolines with high efficiency with broad substrate scopes under mild reaction conditions.

TMSOTf-Catalyzed Reactions of N-Arylynamides with Sulfilimines To Construct 2-Aminoindoles and α-Arylated Amidines.

Here, we disclose an efficient TMSOTf-catalyzed C-H annulation of aryl-terminated N-arylynamides with sulfilimines, leading to the practical assembly of various valuable 2-aminoindoles in generally moderate to excellent yields with a broad range of functional groups, while nonaryl terminated N-arylynamides undergo TMSOTf-catalyzed aminative arylation with sulfilimines providing α-arylated amidines.

Synthesis of Spirocyclohexadienones via Palladium-Catalyzed Dearomatization of Dibenzoxaborins.

The development of Pd(II)-catalyzed dearomatization transformation of dibenzoxaborins with alkynes triggered by transmetalation from boron to palladium has been achieved, leading to the synthesis of spirocyclohexadienones, an important skeleton demonstrating potential biomedical utility. The [3 + 2] spiroannulation exhibits remarkable regioselectivity and broad substrate scope under mild reaction conditions. This methodology employs dibenzoxaborin as a substrate to establish the formal dearomatization of 2-phenylphenol, which poses a formidable energy barrier to the destruction of aromaticity.

Investigation of steric hindrance effect on the interactions between four alkaloids and HSA by isothermal titration calorimetry and molecular docking.

The binding of four alkaloids with human serum albumin (HSA) was investigated by isothermal titration calorimetry (ITC), spectroscopy and molecular docking techniques. The findings demonstrated that theophylline or caffeine can bind to HAS, respectively. The number of binding sites and binding constants are obtained. The binding mode is a static quenching process. The effects of steric hindrance, temperature, salt concentration and buffer solution on the binding indicated that theophylline and HSA have higher binding affinity than caffeine. The fluorescence and ITC results showed that the interaction between HSA and theophylline or caffeine is an entropy-driven spontaneous exothermic process. The hydrophobic force was the primary driving factor. The experimental results were consistent with the molecular docking data. Based on the molecular structures of the four alkaloids, steric hindrance might be a major factor in the binding between HSA and these four alkaloids. This study elucidates the mechanism of interactions between four alkaloids and HSA.