Diversity-oriented and diastereoselective synthesis of diverse polycyclic thieno(2,3-b)-quinoline derivatives using a synergistic strategy.

A cascade spiroannulation of 2-mercaptoquinoline-3-carbaldehydes with α,α-dicyanoalkenes as well as a cascade spiroannulation of 2-mercaptoquinoline-3-carbaldehydes aldehydes with α-bromocarbonyl compounds was investigated based on a synergistic strategy, providing a series of diverse spiro-fused heterocyclic compounds containing more different functional groups. The features of this strategy directed towards molecular complexity and diversity include step economy, mild conditions, and high bond-forming efficiency, but important polycyclic heterocyclic products, which could be transformed into potential biologically interesting heterocyclic structures.

One-Pot Synthesis of Benzimidazo[2,1-b]thiazoline Derivatives through an Addition/Cyclization/Oxidative Coupling Reaction.

A novel and efficient approach to the synthesis of benzimidazo[2,1-b]thiazoline derivatives has been developed through an addition/cyclization/intramolecular oxidative C-H functionalization process. A variety of alkylene benzimidazo[2,1-b] thiazolines were conveniently assembled from the reaction of aryl isothiocyanate and propargylic amine in the presence of Cu(OAc)2 and PIFA at room temperature. The product could be further converted to substituted benzimidazo[2,1-b]thiazole derivatives.

Umpolung Strategy for the Synthesis of Chiral Dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles.

Based on a novel umpolung strategy, an efficient and highly enantioselective cascade aldol/cyclization/tautomerization of the 2-(2-oxoindolin-3-yl)malononitrile to active carbonyl compounds with excellent diastereo- and enantioselectivity has been developed. Also, various enantio-enriched multifunctional dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles with adjacent spiro-stereocenters were conveniently obtained by this novel methodology. Also, the dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles were easily transformed into structurally complex molecules without any effect on the diastereo- and enantioselectivity.

Chemoselective Synthesis of Structurally Diverse 3,4-Dihydroquinazoline-2(1H)-thiones and 4H-Benzo[d][1,3]thiazines.

An efficient, mild, and substrate/catalyst-controlled chemoselective reaction of o-isothiocyanato-(E)-cinnamaldehyde with amines has been established, producing three types of six-membered heterocycles: 2-(4H-benzo[d][1,3]thiazin-4-yl)acetaldehydes, 2-(2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetaldehydes, and (E)-4-(2-methoxyvinyl)-4H-benzo[d][1,3]thiazines. The reaction scopes were quite broad and excellent yield was achieved. This method is extremely efficient and practical and can be conducted on a gram-scale with slightly inferior reactivity under catalyst-free conditions at low cost, making it an ideal alternative to existing methods.

Catalyst-Controlled Switch in Diastereoselectivities: Enantioselective Construction of Functionalized 3,4-Dihydro-2H-thiopyrano[2,3-b]quinolines with Three Contiguous Stereocenters.

A tandem Michael-Henry reaction of 2-mercaptoquinoline-3-carbaldehydes with nitroolefins using hydrogen-bonding-based cooperative organocatalysts for the highly diastereodivergent synthesis of chiral functionalized 3,4-dihydro-2H-thiopyrano[2,3-b]quinolines with three contiguous tertiary stereocenters has been developed.

Enantioselective Synthesis of Ring-Fused Spiroannulated 1,2,3-Thiadiazole Derivatives.

An organocatalytic enantioselective domino α-amination/oxidative coupling/cyclization of thioamides to azodicarboxylates catalyzed by an easily available organic catalyst has been developed. The key step, oxidative coupling, is smoothly fulfilled in air. Optically active spiroannulated 1,2,3-thiadiazole derivatives are obtained with high yields and enantioselectivities for the first time.

Synthesis of 2,3-Dihydrothieno(2,3-b)quinolines and Thieno(2,3-b)- quinolines via an Unexpected Domino Aza-MBH/Alkylation/Aldol Reaction.

An efficient, mild, and convenient method for the preparation of 2,3-dihydrothieno(2,3-b)quinolines and thieno(2,3-b)-quinolines via an unexpected domino aza-Morita-Baylis-Hillman/alkylation/aldol reaction has been developed. The plausible mechanisms for the unexpected reaction are also given.

Tandem Copper-Catalyzed Propargylation/Alkyne Azacyclization/Isomerization Reaction under Microwave Irradiation: Synthesis of Fully Substituted Pyrroles.

A copper-catalyzed and microwave-assisted synthesis of fully substituted pyrroles has been developed. A series of pentasubstituted pyrroles, especially α-arylpyrroles, could be obtained in moderate to good yields (up to 93%) through a tandem propargylation/alkyne azacyclization/isomerization sequence from readily available ß-enamino compounds and propargyl acetates.

Enantioselective Construction of Polyfunctionalized Spiroannulated Dihydrothiophenes via a Formal Thio [3+2] Cyclization.

A formal thio [3+2] cyclization catalyzed by Takemoto's organocatalyst has been reported for the construction of optically active spiroannulated dihydrothiophenes in high yields with excellent regio-, chemo-, diastereo-, and enantioselectivities.

Synthesis and antifungal activities of novel polyheterocyclic spirooxindole derivatives.

A series of spirooxindole tetrahydrofuran derivatives 3 were obtained in moderate to good yields via oxindole derivatives 1 and ß-arylacrylonitrile derivatives 2via base-mediated cascade [3 + 2] double Michael reactions under mild conditions and the application of this method in the synthesis of bioactive analogues, such as functionalized spirooxindole octahydrofuro[3,4-c]pyridine derivatives 4 which contain two new heterocyclic rings and two quaternary carbon centers, has also been developed. Subsequently, antifungal activities of all of the synthesized compounds were evaluated against five phytopathogenic fungi (Rhizoctonia solani, Fusarium semitectum, Alternaria solani, Valsa mali and Fusarium graminearum) using the mycelium growth rate method. The preliminary results showed that the spirooxindole octahydrofuro[3,4-c]pyridine derivative 4 showed higher growth inhibition of Valsa mali and Fusarium graminearum, than spirooxindole tetrahydrofuran derivatives 3. For example, spirooxindole octahydrofuro[3,4-c]pyridine derivative 4ab, having a bromine atom at the meta position of the benzene ring, was the best compound in inhibiting F. g. with an IC50 value of 3.31, in particular with inhibition of 4ab on F. g. being similar to that of the control cycloheximide (IC50 = 3.3 µg mL(-1)).

Development and validation of a QuEChERS-HPLC-DAD method using polymer-functionalized melamine sponges for the analysis of antipsychotic drugs in milk.

The prohibition of antipsychotic drugs in animal foodstuffs has raised significant concerns. In this study, a novel matrix purification adsorbent comprising a polymer (polyaniline and polypyrrole)-functionalized melamine sponge (Ms) was employed for the high performance liquid chromatography-diode array detector (HPLC-DAD) detection of three phenothiazines (chlorpromazine, thioridazine, and promethazine), and a tricyclic imipramine in milk. The as-prepared functionalized Ms was characterized using scanning electron microscopy, Fourier transform infrared spectroscopy, and water contact angle measurements. Excellent linearity with a coefficient of determination (R2) of 0.999 was achieved for all drugs within the concentration range of 0.01-47.00 µg mL-1. The recoveries of the four analytes ranged from 92.1 % to 106.9 % at the three spiked levels. These results demonstrate the successful application of the proposed method for the determination of the four drugs. Cost-effective polymer-functionalized Ms is a viable alternative for matrix purification, enabling rapid determination of drug residues in diverse food samples.

Potential inhibitory effect of Auricularia auricula polysaccharide on advanced glycation end-products (AGEs).

In this study, a novel polysaccharide, AAP-2S, was extracted from Auricularia auricula, and the anti-glycosylation effect of AAP-2S and its underlying mechanisms were investigated using an in vitro BSA-fructose model and a cellular model. The results demonstrated the inhibiting formation of advanced glycation end products (AGEs) in vitro by AAP-2S. Concurrently, it attenuated oxidative damage to proteins in the model, preserved protein sulfhydryl groups from oxidation, reduced protein carbonylation, prevented structural alterations in proteins, and decreased the formation of ß-crosslinked structures. Furthermore, AAP-2S demonstrated metal-chelating capabilities. GC-MS/MS-based metabolomics were employed to analyze changes in metabolic profiles induced by AAP-2S in a CML-induced HK-2 cell model. Mechanistic investigations revealed that AAP-2S could mitigate glycosylation and ameliorate cell fibrosis by modulating the RAGE/TGF-ß/NOX4 pathway. This study provides a foundational framework for further exploration of Auricularia auricular polysaccharide as a natural anti-AGEs agent, paving the way for its potential development and application as a food additive.

Metabolomic analysis of the Puerarin hypoglycemic activity via AMPK-mTOR and PPARγ-NF-κB signaling pathways.

BACKGROUND: Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia, and its increasing prevalence is a global concern. Early diagnostic markers and therapeutic targets are essential for DM prevention and treatment. Pueraria, derived from kudzu root, is used clinically for various symptoms, and its active compound, Puerarin, shows promise in improving insulin resistance and reducing inflammation. PURPOSE: This study aims to evaluate the protective effects of metformin and Puerarin at different doses in an STZ-induced DM mouse model. The intricate metabolites within the serum of STZ-induced diabetic mice were subjected to thorough investigation, thus elucidating the intricate mechanism through which Puerarin demonstrates notable efficacy in the treatment of diabetes. METHODS: An STZ-induced DM mouse model is established. Mice are treated with metformin and puerarin at varying doses. Physiological, biochemical, and histomorphological assessments are performed. Metabolomics analysis is carried out on serum samples from control, DM, metformin, and medium-dose Puerarin groups. Western blot and qRT-PCR technologies are used to validate the mechanisms. RESULTS: The DM mouse model replicates abnormal blood glucose, insulin levels, physiological, biochemical irregularities, as well as liver and pancreas damage. Treatment with metformin and Puerarin restores these abnormalities, reduces organ injury, and modulates AMPK, PPARγ, mTOR, and NF-κB protein and mRNA expression. Puerarin activates the AMPK-mTOR and PPARγ-NF-κB signaling pathways, regulating insulin signaling, glucolipid metabolism, and mitigating inflammatory damage. CONCLUSION: This study demonstrates that Puerarin has the potential to treat diabetes by modulating key signaling pathways. The focus was on the finding that Puerarin has been shown to improve insulin signaling, glucolipid metabolism and attenuate inflammatory damage through the modulation of the AMPK-mTOR and PPARγ-NF-κB pathways. The discovery of Puerarin's favorable protective effect and extremely complex mechanism highlights its prospect in the treatment of diabetes and provides theoretical support for its comprehensive development and utilization.

Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model.

Gene therapy by intratumoral injection is a promising approach for treating solid tumors. However, this approach has limited success due to insufficient distribution of gene vectors used for gene delivery. Previous studies have shown that pulsed-focused ultrasound (pFUS) can enhance both systemic and local delivery of therapeutic agents in solid tumors and other disease models. Here, murine squamous cell carcinoma flank tumors were treated with single intratumoral injection of naked tumor necrosis factor-alpha (TNF-α) plasmid, either with or without a preceding pFUS exposure. The exposures were given at 1 MHz, at a spatial average, temporal peak intensity of 2660 W cm(-2), using 50 ms pulses, given at a pulse repetition frequency of 1 Hz. One hundred pulses were given at individual raster points, spaced evenly over the projected surface of the tumor at a distance of 2 mm. Exposures alone had no effect on tumor growth. Significant growth inhibition was observed with injection of TNF-α plasmid, and tumor growth was further inhibited with pFUS. Improved results with pFUS correlated with larger necrotic regions in histological sections and improved distribution and penetration of fluorescent surrogate nanoparticles. Electron microscopy demonstrated enlarged gaps between cells in exposed tissue, and remote acoustic palpation showed decreases in tissue stiffness after pFUS. Combined, these results suggest pFUS effects may be reducing barriers for tissue transport and additionally lowering interstitial fluid pressure to further improve delivery and distribution of injected plasmid for greater therapeutic effects. This suggests that pFUS could potentially be beneficial for improving local gene therapy treatment of human malignancies.

The traditional Chinese medicine and non-small cell lung cancer: from a gut microbiome perspective.

Non-small cell lung cancer (NSCLC) is one of the most serious diseases affecting human health today, and current research is focusing on gut flora. There is a correlation between intestinal flora imbalance and lung cancer, but the specific mechanism is not clear. Based on the "lung and large intestine being interior-exteriorly related" and the "lung-intestinal axis" theory. Here, based on the theoretical comparisons of Chinese and western medicine, we summarized the regulation of intestinal flora in NSCLC by active ingredients of traditional Chinese medicine and Chinese herbal compounds and their intervention effects, which is conducive to providing new strategies and ideas for clinical prevention and treatment of NSCLC.

Eucommia Bark/Leaf Extract Improves Lipid Metabolism Disorders by Affecting Intestinal Microbiota and Microbiome-Host Interaction in HFD Mice.

Eucommia bark contains many bioactive compounds and has anti-hyperlipidemic effects. However, due to the slow growth rate of the plant, there is a limited supply of this resource. Studies have demonstrated that Eucommia leaves contain active ingredients similar to those of Eucommia bark and also have anti-hyperlipidemic effects. It is not currently clear whether Eucommia leaf can be used as a substitute for Eucommia bark. Furthermore, their mechanism of action for anti-hyperlipidemia by improving the structure of the gut microbiota is also unclear. We aimed to determine the composition of the active ingredients in EBE and ELE by HPLC, establish an HFD-induced hyperlipidemia model, and combine fecal microbiota transplantation (FMT) experiments to investigate the mechanism of EBE/ELE anti-hyperlipidemia by modifying the structure of intestinal microbiota, as well as to compare the effects of EBE and ELE. Our results showed that EBE and ELE contained similar active ingredients and significantly alleviated lipid metabolism disorders and blood glucose levels in the HFD-induced hyperlipidemia model. In this study, EBE and ELE significantly reduced the relative abundance of Desulfovibrionaceae and Erysipelotrichaceae and significantly increased the relative abundance of Ruminococcaceae. They also promoted the production of short-chain fatty acids (SCFAs) and activated the gene expression of the SCFA receptors G protein-coupled receptor 41 (GPR41) and GPR43. In addition, EBE and ELE can significantly increase the expression of the fasting-induced adipose factor (Fiaf) gene in the colon and inhibit the secretion of lipoprotein lipase (LPL) in the liver, thereby inhibiting triglyceride (TG) synthesis. They also significantly activate the expression of GPR41 and GPR43 genes in the epididymal fat tissue, leading to reduced lipid accumulation in adipocytes. These effects on the target genes were associated with changes in the abundance of Desulfovibrionaceae, Erysipelotrichaceae, and Ruminococcaceae bacteria in the intestinal microbiota. Thus, regulating the relative abundance of these microbes may serve as prospective targets for EBE/ELE to influence the Fiaf-LPL gut-liver axis and the SCFAs-GPR41/GPR43 gut-fat axis. In addition, there was no significant difference in the anti-hyperlipidemic effects of ELE and EBE, suggesting that Eucommia leaf may be a suitable alternative to Eucommia bark for managing hyperlipidemia by regulating the structure of the intestinal microbiota. These findings suggest that Eucommia leaves have great potential for development as a functional food with lipid-lowering properties.

Lipid-Lowering Effects of a Novel Polysaccharide Obtained from Fuzhuan Brick Tea In Vitro.

Lipid accumulation causes diseases such as obesity and abnormal lipid metabolism, thus impairing human health. Tea polysaccharide is one of the natural, active substances that can lower lipid levels. In this paper, an oleic-acid-induced HepG2 cell model was established. The lipid-lowering effects of a novel group of Fuzhuan brick tea polysaccharides (FTPs)-obtained from Fuzhuan brick tea-were examined in vitro. The monosaccharide composition of FTP3 was Glc, Gal, Ara, Man, Rha, GalAc, GlcAc, and Xyl with a molar ratio of 23.5:13.2:9.0:5.5:5.4:2.7:1.3:1.0, respectively. A molecular weight of 335.68 kDa was identified for FTP3. HepG2 cells treated with FTP3 achieved a prominent lipid-lowering effect compared with cells treated with oleic acid. Images of the Oil Red O staining treatment showed that FTP3-treated groups had significantly fewer red fat droplets. TC and TG levels were lower in FTP3-treated groups. FTP3 alleviated lipid accumulation in HepG2 cells, activated AMPK, and decreased the SREBP-1C and FAS protein expressions associated with fatty acid synthesis. FTP3 holds promising potential for its lipid-lowering effects.

Structure Characterization, In Vitro Antioxidant and Anti-Tumor Activity of Sulfated Polysaccharide from Siraitia grosvenorii.

From Siraitia grosvenorii, a natural polysaccharide named SGP-1 was discovered, and its purity was determined to be 96.83%. Its structure is a glucan with 4-, 6- and 4,6-linked glucose units. In this paper, the sulfated derivative S-SGP of SGP-1 was prepared by the chlorosulfonic acid method. The sulfated derivatives were analyzed by Fourier transform infrared spectroscopy (FT-IR), gel permeation chromatography (GPC), and scanning electron microscopy (SEM). The degree of substitution (DS) of the polysaccharide is 0.62, and the weight average molecular weight (Mw) is 1.34 × 104 Da. While retaining the morphological characteristics of polysaccharides, S-SGP appeared a large number of spherical structures and strong intermolecular forces. The in vitro activity study of S-SGP showed that the sulfated derivatives had the ability to scavenge DPPH radicals, hydroxyl radicals and superoxide anions, and the scavenging power tended to increase with the increase in polysaccharide concentration. It can inhibit the growth of human hepatoma cells (HepG2), human breast cancer cells (MDA-MB-231) and human non-small cell lung cancer cells (A549) in vitro. In addition, the treatment of A549 cells with sulfuric acid derivatives can decrease the mitochondrial membrane potential, induce apoptosis, and alter the expression of apoptosis-related mRNA and protein.

Asymmetric catalytic [4 + 1] annulations catalyzed by quinidine: enantioselective synthesis of multi-functionalized isoxazoline N-oxides.

A highly regio-, chemo-, diastereo- and enantioselective organocatalytic [4 + 1] annulation of 2-halo-1,3-dicarbonyl compounds with Morita-Baylis-Hillman adducts catalyzed by commercially available, low cost quinidine for the preparation of synthetically unique and medicinally multi-functionalized isoxazoline N-oxides with three stereogenic centers including adjacent quaternary and tertiary stereocenters has been developed. Notably, the unexpected product ethyl 2-((tert-butyldimethylsilyl)oxy)-2-(5,5-diacetyl-3-((methylsulfonyl)oxy)-4-phenylisoxazolidin-3-yl)acetate (8) bearing a quaternary stereocenter and two tertiary stereocenters was obtained from the undocumented 5,5-diacetyl-3-(2-ethoxy-1-hydroxy-2-oxoethyl)-4-phenyl-4,5-dihydroisoxazole 2-oxide (4ba).

Construction of functionalized 2,3-dihydro-1,4-benzoxazines via [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds with imines.

A series of functionalized 2,3-dihydro-1,4-benzoxazines were obtained in moderate to excellent yields via domino [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds 2 with imines 1 under mild conditions and the application of this method in the synthesis of bioactive analogues, such as functionalized tetracyclic-1,4-benzoxazines which contain two new heterocyclic rings and one quaternary carbon center has also been developed.