Visible-Light-Promoted Cascade Coupling of 2-Isocyanonaphthalenes with Elemental Sulfur and Amines to Construct Naphtho[2,1-d]thiazol-2-Amines.

A visible-light-induced strategy has been explored for the synthesis of naphtho[2,1-d]thiazol-2-amines through ortho-C-H sulfuration of 2-isocyanonaphthalenes with elemental sulfur and amines under external photocatalyst-free conditions. This three-component reaction, which utilizes elemental sulfur as the odorless sulfur source, molecular oxygen as the clean oxidant, and visible light as the clean energy source, provides a mild and efficient approach to construct a series of naphtho[2,1-d]thiazol-2-amines. Preliminary mechanistic studies indicated that visible-light-promoted photoexcitation of reaction intermediates consisting of thioureas and DBU might be involved in this transformation.

Visible-Light Photoredox-Catalyzed Difunctionalization of Alkynes with Quinoxalin-2(1H)-Ones, P4S10, and Alcohols.

Visible-light photoredox-catalyzed method has been developed for the synthesis of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates via direct difunctionalization of alkynes with quinoxalin-2(1H)-ones, P4S10 and alcohols. This four-component reaction could be carried out under metal-free and mild conditions, affording a number of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates in moderate to good yields with Z-isomers as the major products. Photocatalytic radical mechanism is proposed based on the results of radical trapping and fluorescence quenching experiments.

Copper-Catalyzed Three-Component Tandem Reaction of Alkynes, α-Diazo Esters, and TMSN3 to Access N-Substituted 1,2,3-Triazoles.

An efficient copper-catalyzed three-component tandem reaction of alkynes, α-diazo esters, and TMSN3 to construct triazoles has been developed. Through this strategy, a number of diverse N-substituted 1,2,3-triazoles were conveniently obtained in moderate to good yields from simple and readily available starting materials using K2CO3 as the base. The mechanism of the tandem Cu-catalyzed azide-alkyne cycloaddition (CuAAC) and Cu-carbenoid-participated C-N coupling reaction has been investigated.

Rapid screening of α-glucosidase inhibitors in Hypericum perforatum L. using bio-affinity chromatography coupled with UPLC/MS.

α-glucosidase inhibitors (AGIs) are widely used for the treatment of type 2 diabetes, but their side effects have made it to develop novel and alternative AGIs immediately. In this study, the extract of Hypericum perforatum L. (HPE) has been confirmed to have α-glucosidase inhibitory activity in vitro and in vivo. Seven active compounds, rutin, hyperoside, isoquercitrin, avicularin, quercitrin, quercetin, and biapigenin, were screened based on a bio-affinity chromatography column with α-glucosidase enzyme-conjugated solid phase and UPLC/MS, which exhibited excellent α-glycosidase inhibitory effects by the determined IC50 values. The mechanism of α-glycosidase inhibitory activity of biapigenin was studied for the first time. The results showed that biapigenin was a high-potential, reversible, and mixed enzyme inhibitor. Analysis by molecular docking further revealed that hydrophobic interactions were generated by interactions between biapigenin and amino acid residues LYS156, PHE303, PHE314, and LEU313. In addition, hydrogen bonding occurred between biapigenin and α-glucosidase amino acid residues ASP307, SER241, and LYS156. This research identified that biapigenin could be a novel AGI and further applied to the development of potential anti-diabetic drugs. Furthermore, our studies established a rapid in vitro screening method for AGIs from plants.

Two new polycyclic polyprenylated acylphloroglucinols derivatives from Hypericum acmosepalum.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) were mainly obtained from the plants of Hypericum genus of Guttiferae family, and possessed intriguing chemical structures and appealing biological activities. Two new PPAPs derivatives, hyperacmosin C (1) and hyperacmosin D (2) were isolated from H. acmosepalum. Their structures were established by NMR, HREIMS, and experimental electronic circular dichroism spectra. Besides, compound 1 showed significant hepatoprotective activity at 10 µM against paracetamol-induced HepG2 cell damage and compound 2 could moderately increase the relative glucose consumption.

Inhibitory Activity and Mechanism Investigation of Hypericin as a Novel α-Glucosidase Inhibitor.

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC50) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10-5 M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.

Metal-Free Trifluoroalkylation of Quinoxalin-2(1H)-ones with Unactivated Alkenes and Langlois' Reagent.

A K2S2O8-mediated three-component protocol has been developed for the construction of 3-trifluoroalkylated quinoxalin-2(1H)-ones under metal-free conditions. The present reaction could be accomplished through the trifluoroalkylation of quinoxalin-2(1H)-ones with unactivated alkenes and Langlois' reagent (CF3SO2Na), which provided a highly attractive approach to access a series of biologically important 3-trifluoroalkylated quinoxalin-2(1H)-ones.

Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study.

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rather nucleophilic. A Hammett plot analysis of the addition reactions of the two radicals to substituted styrenes clearly support the nucleophilicity of benzoyl, but in the case of acetonyl, no satisfactory linear correlation with a single substituent-related parameter was found. Computational calculations helped to rationalize this effect, and a good linear correlation was found with a combination of polar parameters (σ+ ) and the radical stabilization energies of the formed intermediates. Based on the calculated philicity indices for benzoyl and acetonyl, a quantitative comparison of these two radicals with many other reported radicals is possible, which may help to predict the reactivities of other aromatic radical substitution reactions.

Metal-Free Catalytic Synthesis of Thiocarbamates Using Sodium Sulfinates as the Sulfur Source.

A novel molecular iodine-catalyzed protocol for the construction of thiocarbamates from readily available sodium sulfinates, isocyanides, and water has been described. The present methodology offers a facile and practical route to a variety of thiocarbamates in moderate to good yields with favorable functional group tolerance by use odorless sodium sulfinates as the sulfur source. The mechanistic studies suggest the present transformation involves a radical process.

Catalyst-free synthesis of α-thioacrylic acids via cascade thiolation and 1,4-aryl migration of aryl alkynoates at room temperature.

A simple and facile catalyst-free method for the construction of α-thioacrylic acids has been developed from readily-available aryl alkynoates and thiols at room temperature. Various α-thioacrylic acids could be conveniently and efficiently obtained in moderate to good yields via cascade thiolation and 1,4-aryl migration of aryl alkynoates in the absence of any catalyst and additive.

Target separation of flavonoids from Saxifraga tangutica using two-dimensional hydrophilic interaction chromatography/reversed-phase liquid chromatography.

An orthogonally (80.3%) preparative two-dimensional hydrophilic interaction chromatography/reversed-phase liquid chromatography method has been established for the isolation and purification of flavonoids from Saxifraga tangutica. Initially, flavonoids were enriched by means of a middle-pressure chromatographic tower (containing middle chromatogram isolated gel). In the first dimension, a XION preparative column was used to separate the flavonoid fractions under the guidance of characteristic ultraviolet absorption spectra of flavonoids and nine flavonoid fractions were obtained. Then, the coeluted flavonoid fractions were selected for further purification via reversed-phase liquid chromatography with the parent ion peak of quercetin (303), kaempferol (287), or isorhamnetin (317). Several flavonoids could be separated from each hydrophilic interaction chromatography fraction; furthermore, flavonoids with poor resolution in one-dimensional liquid chromatography were isolated in two-dimensional liquid chromatography due to the orthogonality. In addition, this technique was valuable for trace flavonoids, which were concentrated in the first stage and separated in the second stage. In total, 18 flavonoids with either quercetin, kaempferol, or isorhamnetin parent nuclei were targetedly obtained, and 15 flavonoids were obtained for the first time from S. tangutica. These results established that the off-line two-dimensional hydrophilic interaction chromatography/reversed-phase liquid chromatography technique was efficient for the isolation of flavonoids from Saxifraga tangutica.

Efficient Separation of Four Antibacterial Diterpenes from the Roots of Salvia Prattii Using Non-Aqueous Hydrophilic Solid-Phase Extraction Followed by Preparative High-Performance Liquid Chromatography.

An efficient preparative procedure for the separation of four antibacterial diterpenes from a Salvia prattii crude diterpenes-rich sample was developed. Firstly, the XION hydrophilic stationary phase was chosen to separate the antibacterial crude diterpenes-rich sample (18.0 g) into three fractions with a recovery of 46.1%. Then, the antibacterial fractions I (200 mg), II (200 mg), and III (150 g) were separated by the Megress C18 preparative column, and compounds tanshinone IIA (80.0 mg), salvinolone (62.0 mg), cryptotanshinone (70.0 mg), and ferruginol (68.0 mg) were produced with purities greater than 98%. The procedure achieved large-scale preparation of the four diterpenes with high purity, and it could act as a reference for the efficient preparation of active diterpenes from other plant extracts.

Metal-free Oxidative Coupling of Aromatic Alkenes with Thiols Leading to (E)-Vinyl Sulfones.

A facile I2O5-mediated direct oxidative coupling of aromatic alkenes with thiols toward vinyl sulfones has been developed under metal-free conditions. This methodology provides a convenient and efficient approach to various (E)-vinyl sulfones from readily available starting materials with excellent regioselectivity. The present oxidative coupling reaction, not only expands the scope of functionalization of alkenes with thiols, but also makes it a practical and powerful complement to traditional methods for the synthesis of (E)-vinyl sulfones.

Chinese Rural Kindergarten Teachers' Work-Family Conflict and Their Turnover Intention: The Role of Emotional Exhaustion and Professional Identity.

The loss of rural kindergarten teachers has become a common social concern in China, which is of great importance to the development of preschool education. This study conducted a survey of 2944 kindergarten teachers in mainland China, to explore the relationship between work-family conflict and turnover intention, the mediating effect of emotional exhaustion, and the moderating effect of professional identity. The study used the work-family conflict questionnaire, the emotional exhaustion scale, the turnover intention questionnaire, and the professional identity questionnaire. The results showed that (1) work-family conflict significantly predicted turnover intention; (2) emotional exhaustion played a mediating role between work-family conflict and turnover intention; and (3) professional identity moderated the latter half path of the mediation model, that is, strong professional identity alleviated the indirect predicting effect of work-family conflict on turnover intention through emotional exhaustion. The results clarified the influencing mechanism of work-family conflict on turnover intention, which could help improve rural preschool teachers' positive emotions and reducing turnover.

Rhodiosin from Rhodiola crenulata effectively alleviate postprandial hyperglycemia by inhibiting both the activity and production of α­glucosidase.

BACKGROUND: Effective control of postprandial blood glucose (PBG) level is essential for the prevention and treatment of diabetes and its complications. Several flavonoids have attracted much attention due to their significant PBG-lowering effects. However, there is still a certain gap in the in vivo hypoglycemic activity of most flavonoids compared to first-line drugs available on the market, and are still lack of the PBG-lowering effects of 8-hydroxyflavones and their structure-activity relationship. PURPOSE: Evaluate hypoglycemic effects of 8-hydroxyflavones from Rhodiola crenulata in vitro and in vivo, especially comparatively analyze the relationship between hypoglycemic effects and flavonoid configuration and reveal the possible mechanism of 8-hydroxyflavones in lowering hyperglycemia. METHODS: Starch, maltose, sucrose, and glucose tolerance tests in both diabetic and normal mice were used to evaluate and compare the hypoglycemic effects of 8-hydroxyflavones rhodiosin (RHS), rhodionin (RHN), and herbacetin (HBT). Molecular docking, enzyme kinetics, and immunofluorescence analysis were used to research the possible hypoglycemic mechanisms of 8-hydroxyflavones. RESULTS: RHS (5 and 10 mg/kg) could efficiently decrease PBG levels in both normal and diabetes mice. Moreover, RHS, RHN, and HBT all had significant PBG-lowering effects in transgenic diabetes mice, and the effects were equivalent to or stronger than acarbose. Further mechanism research indicated that 8-hydroxyflavones achieved PBG-lowering effects by inhibiting both the activity and production of glycosidase. Notably, we have innovatively discovered that inhibiting the expression of glycosidases rather than just their activities may be a new target for hypoglycemic drugs. CONCLUSION: We have firstly comprehensively and systematically clarified PBG-lowering effects of 8-hydroxyflavones from Rhodiola crenulata, and revealed their structure-activity relationships and hypoglycemic mechanisms. The study demonstrated that the substitution of 8-hydroxy groups in flavonoids could significantly enhance their hypoglycemic effects, which were equivalent to or stronger than commercially available drug acarbose. 8-Hydroxyflavones could be used as therapeutic or health drugs with significant potential to reduce postprandial hyperglycemia.

Characterization of alkaloids and phenolics in Nitraria roborowskii Kom. fruit by UHPLC-triple-TOF-MS/MS and its sucrase and maltase inhibitory effects.

Nitraria roborowskii Kom (NRK), with high economic and ecological value, is mainly distributed in the Qaidam Basin, China. However, research on its chemical components and bioactivities is still rare. In this study, its chemical constituents (52) including 10 ß-carboline alkaloids, nine cyclic peptides, three indole alkaloids, five pyrrole alkaloids, eight phenolic acids and 17 flavonoids were identified tentatively using UPLC-triple-TOF-MS/MS. Notablely, one new ß-carboline alkaloid and five new cyclic peptides were confirmed using MS/MS fragmentation pathways. In addition, experiments in vitro indicated that NRK-C had strong maltase and sucrase inhibitory activities (IC50 of 0.202 and 0.103 mg/mL, respectively). Polysaccharide tolerance experiments confirmed NRK-C (400 mg/kg) was associated with decreased postprandial blood glucose (PBG) in diabetic mice. These results suggested that NRK fruit might be used as a functional ingredient in food products.

Extract of Silphium perfoliatum L. improve lipid accumulation in NAFLD mice by regulating AMPK/FXR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Globally, the incidence rate and number of patients with nonalcoholic fatty liver disease are increasing, which has become one of the greatest threats to human health. However, there is still no effective therapy and medicine so far. Silphium perfoliatum L. is a perennial herb native to North America, which is used to improve physical fitness and treat liver and spleen related diseases in the traditional medicinal herbs of Indian tribes. This herb is rich in chlorogenic acids, which have the functions of reducing blood lipids, losing weight and protecting liver. However, the effect of these compounds on nonalcoholic fatty liver disease remains unclear. AIM OF THE STUDY: Clarify the therapeutic effects and mechanism of the extract (CY-10) rich in chlorogenic acid and its analogues from Silphium perfoliatum L. on non-alcoholic fatty liver disease, and to determine the active compounds. MATERIALS AND METHODS: A free fatty acid-induced steatosis model of HepG2 cells was established to evaluate the in vitro activity of CY-10 in promoting lipid metabolism. Further, a high-fat diet-induced NAFLD model in C57BL/6 mice was established to detect the effects of CY-10 on various physiological and biochemical indexes in mice, and to elucidate the in vivo effects of the extract on regulating lipid metabolism, anti-inflammation and hepatoprotection, and nontarget lipid metabolomics was performed to analyze differential metabolites of fatty acids in the liver. Subsequently, western blotting and immunohistochemistry were used to analyze the target of the extract and elucidate its mechanism of action. Finally, the active compounds in CY-10 were elucidated through in vitro activity screening. RESULTS: The results indicated that CY-10 significantly attenuated lipid droplet deposition in HepG2 cells. The results of in vivo experiments showed that CY-10 significantly reduce HFD-induced mouse body weight and organ index, improve biochemical indexes, oxidation levels and inflammatory responses in the liver and serum, thereby protecting the liver tissue. It can promote the metabolism of unsaturated fatty acids in the liver and reduce the generation of saturated fatty acids. Furthermore, it is clarified that CY-10 can promote lipid metabolism balance by regulating AMPK/FXR/SREPB-1c/PPAR-γ signal pathway. Ultimately, the main active compound was proved to be cryptochlorogenic acid, which has a strong promoting effect on the metabolism of fatty acids in cells. Impressively, the activities of CY-10 and cryptochlorogenic acid were stronger than simvastatin in vitro and in vivo. CONCLUSION: For the first time, it is clarified that the extract rich in chlorogenic acids and its analogues in Silphium perfoliatum L. have good therapeutic effects on non-alcoholic fatty liver disease. It is confirmed that cryptochlorogenic acid is the main active compound and has good potential for medicine.

Separation and purification of five phenylpropanoid glycosides from Lamiophlomis rotata (Benth.) Kudo by a macroporous resin column combined with high-speed counter-current chromatography.

Five phenylethanoid glycosides (PhGs), forsythoside B, verbascoside, alyssonoside, isoverbascoside, and leucosceptoside B, were isolated and purified from Lamiophlomis rotata (Benth.) Kudo by high-speed counter-current chromatography (HSCCC) combined with macroporous resin (MR) column separation. In the present study, the two-phase solvent system composed of ethyl acetate/n-butanol/water (13:3:10, v/v/v) was used for HSCCC separation. A total of 27 mg of forsythoside B, 41 mg of verbascoside, 29 mg of alyssonoside, 23 mg of isoverbascoside, and 13 mg of leucosceptoside B with purities of 97.7, 99.2, 99.5, 99.3, and 97.3%, respectively, were obtained in a one-step separation within 4 h from 150 mg of crude extract. The recoveries of the five PhGs after MR-HSCCC separation were 74.5, 76.5, 72.5, 76.4, and 77.0%, respectively. The chemical structures of all five compounds were identified by (1) H and (13) C NMR spectroscopy.

Preparative isolation and purification of three stilbene glycosides from the tibetan medicinal plant Rheum tanguticum maxim. Ex Balf. by high-speed counter-current chromatography.

INTRODUCTION: Stilbene glycosides are the primary constituents of Rheum tanguticum Maxim. ex Balf., to which different bioactivities has been attributed, including: anti-HIV, anti-oxidant, anti-tumour, anti-malarial, and anti-allergy activity. However, effective methods for the isolation and purification of stilbene glycosides, such as trans-rhapontin, cis-rhapontin and trans-desoxyrhaponticin, from this herb are not currently available. OBJECTIVE: To develop an efficient method for the preparative isolation and purification of three stilbene glycosides from Rheum tanguticum Maxim. ex Balf. via high-speed counter-current chromatography (HSCCC). METHODS: A solvent system composed of chloroform:n-butanol:methanol:water (4:1:3:2, v/v/v/v) was developed for the separation. The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. The flow rate was 1.8 mL/min. The apparatus was controlled at 800 rpm and 25 °C, and the effluent was monitored at 280 nm. Chemical constituents were analysed by high-performance liquid chromatography (HPLC), and their structures were identified by ¹H- and ¹³C-NMR. RESULTS: Under the optimised conditions, 25.5 mg trans-rhapontin, 16.0 mg cis-rhapontin and 20.5 mg trans-desoxyrhaponticin were separated from 80 mg crude sample; the isolates had purities of 99.6, 97.2 and 99.2%, respectively. CONCLUSION: A simple and efficient HSCCC method has been optimised for the preparative separation of stilbene glycosides from Rheum tanguticum Maxim. ex Balf.

Targeted isolation of cyclooxygenase-2 inhibitors from Saussurea obvallata using affinity ultrafiltration combined with preparative liquid chromatography.

Saussurea obvallata (S. obvallata) is widely used in Qinghai-Tibet Plateau with high medicinal and edible values of reducing inflammation. But, the individual components and mechanisms of action still ill-defined. In this work, an integrated method using affinity ultrafiltration combined with preparative liquid chromatography was developed to identify and separate cyclooxygenase-2 (COX-2) inhibitors from S. obvallata. The sample was pretreated using on-line medium pressure liquid chromatography to yield the active fraction. Then, the potential COX-2 ligands were screened out using affinity ultrafiltration from the targeted fraction and the identified compounds were isolated via preparative liquid chromatography. As a result, four main compounds, coniferin (1), syringin (2), roseoside (3) and grasshopper ketone (4) were targeted isolated with IC50 values of 12.34 ± 1.81, 4.04 ± 0.43, 13.91 ± 2.46 and 7.97 ± 1.21 µM, respectively. Results of this work demonstrated that the developed strategy was effective for the targeted separation of COX-2 inhibitors from natural product extracts.