Pro-aromaticity Enabled Dealkenylative Functionalizations via Photo-Excitation and Oxidation.

A general and practical approach for diverse dealkenylative functionalization of olefin-containing substrates has been developed through the one-pot formation and utilization of pro-aromatic 1,4-dihydropyridazines using tetrazine as the key cycloaddition reagent. Triggered by either excitation or oxidation, the targeted C-C bonds in the 1,4-dihydropyridazine intermediates could be readily cleaved to generate alkyl radicals for subsequent transformations. Diverse carbon-carbon and carbon-hetero bond forming protocols, including Giese-type addition, hydrazination, borylation, Minisci-type alkylation, copper-catalyzed NH alkylation, acylation, alkynylation, cyanation, and azidation, are achieved in a highly modular fashion.

Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies.

Grayanane diterpenoids contain over 300 highly oxidized and structurally complex members, many of which possess important biological activities. Full details are provided for the development of the concise, enantioselective and divergent total syntheses of grayanane diterpenoids and (+)-kalmanol. The unique 7-endo-trig cyclization based on a bridgehead carbocation was designed and implemented to construct the 5/7/6/5 tetracyclic skeleton, demonstrating the practical value of the bridgehead carbocation-based cyclization strategy. Extensive studies of late-stage functional group manipulation were performed to forge the C1 stereogenic center, during which a photoexcited intramolecular hydrogen atom transfer reaction was discovered and the mechanism was further studied through density functional theory (DFT) calculations. The biomimetic 1,2-rearrangement from the grayanoid skeleton provided a 5/8/5/5 tetracyclic framework and resulted in the first total synthesis of (+)-kalmanol.

Scalable Total Synthesis of (-)-Triptonide: Serendipitous Discovery of a Visible-Light-Promoted Olefin Coupling Initiated by Metal-Catalyzed Hydrogen Atom Transfer (MHAT).

An efficient and scalable total synthesis of (-)-triptonide is accomplished based on a metal-catalyzed hydrogen atom transfer (MHAT)-initiated radical cyclization. During the optimization of the key step, we discovered that blue LEDs significantly promoted the efficiency of reaction initiated by Co(TPP)-catalyzed MHAT. Further exploration and optimization of this catalytic system led to development of a dehydrogenative MHAT-initiated Giese reaction.

Total Synthesis of (+)-Mutilin: A Transannular [2+2] Cycloaddition/Fragmentation Approach.

A new and enantioselective total synthesis of the diterpenoid (+)-mutilin is described. Following a Claisen rearrangement approach to construct the 6,9-bicycle, a transannular [2+2] photocycloaddition and the ensuing ring-opening reaction were implemented to forge the characteristic 5-6-8 propellane-like skeleton. Subsequent late-stage alkylations and reduction completed the synthesis.

Dealkenylative Ni-Catalyzed Cross-Coupling Enabled by Tetrazine and Photoexcitation.

A new and general method to functionalize the C(sp3)-C(sp2) bond of alkyl and alkene linkages has been developed, leading to the dealkenylative generation of carbon-centered radicals that can be intercepted to undergo Ni-catalyzed C(sp3)-C(sp2) cross-coupling. This one-pot protocol leverages the easily procured alkene feedstocks for organic synthesis with excellent functional group compatibility without the need for a photoredox catalyst.

Total Synthesis of (-)-Batrachotoxinin A: A Local-Desymmetrization Approach.

An enantioselective total synthesis of (-)-batrachotoxinin A is accomplished based on a key photoredox coupling reaction and the subsequent local-desymmetrization operation. After the expedient assembly of the highly oxidized steroid skeleton, a delicate sequence of redox manipulations was carried out to deliver a late-stage intermediate on gram scale-and ultimately (-)-batrachotoxinin A in an efficient manner.

Enantioselective syntheses and application of 4-epi-galiellalactone and the corresponding activity-based probe: from strained bicycles to strained tricycles.

The [6,5,5] tricyclic fungal metabolite galiellalactone is a Michael acceptor that has been demonstrated to be a covalent inhibitor for Signal Transducer and Activator of Transcription 3 (STAT3). Recognizing the ring strain associated with the skeleton of this natural product, we utilized 1R-5S-bicyclo[3.1.0]hexan-2-one as the starting material and developed two novel approaches to accomplish the enantioselective total synthesis of the C4 epimer of galiellalactone in 5 and 7 steps, respectively, which capitalized on an efficient radical cyclization/fragmentation cascade reaction. Furthermore, an activity-based probe of 4-epi-galiellalactone with a terminal alkyne tag was successfully prepared to enable the experiments of activity-based protein profiling (ABPP). Through western blot and proteomic analysis, we not only confirmed the known target STAT3, but also identified a new target protein ataxin-7, which formed a covalent bond with the probe in intact cells via the Cys-129 residue.

Redox-Active Ligand Assisted Multielectron Catalysis: A Case of CoIII Complex as Water Oxidation Catalyst.

Water oxidation is the key step in both natural and artificial photosynthesis to capture solar energy for fuel production. The design of highly efficient and stable molecular catalysts for water oxidation based on nonprecious metals is still a great challenge. In this article, the electrocatalytic oxidation of water by Na[(L4-)CoIII], where L is a substituted tetraamido macrocyclic ligand, was investigated in aqueous solution (pH 7.0). We found that Na[(L4-)CoIII] is a stable and efficient homogeneous catalyst for electrocatalytic water oxidation with 380 mV onset overpotential in 0.1 M phosphate buffer (pH 7.0). Both ligand- and metal-centered redox features are involved in the catalytic cycle. In this cycle, Na[(L4-)CoIII] was first oxidized to [(L2-)CoIIIOH] via a ligand-centered proton-coupled electron transfer process in the presence of water. After further losing an electron and a proton, the resting state, [(L2-)CoIIIOH], was converted to [(L2-)CoIV═O]. Density functional theory (DFT) calculations at the B3LYP-D3(BJ)/6-311++G(2df,2p)//B3LYP/6-31+G(d,p) level of theory confirmed the proposed catalytic cycle. According to both experimental and DFT results, phosphate-assisted water nucleophilic attack to [(L2-)CoIV═O] played a key role in O-O bond formation.

Total Synthesis of (+)-Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization.

A new method for one-step construction of the tetracyclic core structure of the indole alkaloid (+)-minfiensine was developed utilizing a palladium-catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)-minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.

[Effects of Straw and Biochar Amendments on Characteristics of Soil Fungal Community and Organic Carbon Pool in Jasminum sambac Garden].

In order to elucidate the changes in the soil fungal community and soil organic carbon components of a Jasminum sambac garden after straw and biochar application, we measured the organic carbon components and soil fungal community of the 0-15 cm soil layer in a J. sambac garden, which was divided into a control group, straw treatment group, and biochar treatment group. The carbon pool management index （CPMI） was also calculated. The results showed that the diversity of the soil fungal community was decreased after straw and biochar application, and the structure of dominant fungal genera was changed in each treatment. The soil fungal community structure in the biochar treatment was significantly different from that in the straw treatment and control groups. Redundancy analysis （RDA） showed that soil fungal community structure was mainly affected by soil bulk density, C∶N, salinity, and TN. Secondly, compared with that in the control group, soil labile organic carbon （LOC） in the straw treatment group was significantly increased by 87.44% （P<0.05）, whereas soil dissolved organic carbon （DOC） and microbial biomass carbon （MBC） in the biochar treatment group were significantly increased by 22.27% and 23.17% （P<0.05）, respectively. Further, compared with that in the control group, the carbon pool activity （L） under straw treatment was significantly increased （P<0.05）, and the carbon pool index （CPI） under biochar treatment was significantly increased （P<0.05）. Spearman correlation analysis showed that the distribution characteristics of soil organic carbon active components were regulated by the dominant fungi. FUNGuild functional prediction results showed that saprophytic and its facultative nutritional fungi had an important impact on soil organic carbon active components and carbon pool management index after straw and biochar application.

Identification, characterization and hypolipidemic effect of novel peptides in protein hydrolysate from Protaetia brevitarsis larvae.

The proteins were mainly derived from Protaetia brevitarsis larval extracts obtained using two empty intestine methods (traditional static method: TSM or salt immersion stress method: SISM) and extraction solvents (water: W or 50 % water-ethanol: W:E), and the proteins were used as objects to investigate the effect of emptying intestine methods on hypolipidemic peptides. The results revealed that the F-2 fractions of protein hydrolysate had stronger in vitro hypolipidemic activity, with the peptides obtained by SISM possessing a stronger cholesterol micelle solubility inhibition rate, especially in SISM-W:E-P. Moreover, a total of 106 peptides were tentatively identified, among which SISM identified more peptides with an amino acid number < 8. Meanwhile, five novel peptides (YPPFH, YPGFGK, KYPF, SPLPGPR and VPPP) exhibited good hypolipidemic activity in vitro and in vivo, among which YPPFH, VPPP and KYPF had strong inhibitory activities on pancreatic lipase (PL) and cholesteryl esterase (CE), and KYPF, SPLPGPR and VPPP could significantly reduce the TG content in Caenorhabditis elegans. Thus, P. brevitarsis can be developed as a naturally derived hypolipidemic component for the development and application in functional foods.

Combination therapy with toripalimab and anlotinib in advanced esophageal squamous cell carcinoma: A case report.

BACKGROUND: Toripalimab and anlotinib have shown good response in esophageal cancer, with high objective response rate and progression free survival. Thus, they have been approved as second-line or above-line therapy for advanced or unresectable esophageal carcinoma. Combination of these two drugs may have synergistic effects, but evidence of which is lacking. CASE SUMMARY: Here, we report on a 73-year-old male, newly diagnosed with advanced esophageal squamous cell carcinoma (ESCC), who received a combination of toripalimab and anlotinib. Complete response was achieved after treatment for 3 mo and remission was maintained up to 14 mo. CONCLUSION: The combination therapy of toripalimab and anlotinib is a promising treatment for unresectable ESCC and related clinical trials are warranted.

Characterization of bioactives and in vitro biological activity from Protaetia brevitarsis larval extracts obtained by different pretreatment extractions.

Intestinal contents affect the characterization of edible insect bioactive compounds. Two empty intestine methods, namely, traditional static method (TSM) or salt immersion stress method (SISM), associated with extraction solvents water (W), 50 % water-ethanol (W:E) or 100 % ethanol (E), were used to obtain six Protaetia brevitarsis larval extracts. The total flavonoid content (TFC) in the W:E extracts was significantly higher than that in the W and E extracts, with TSM-W:E the highest (p < 0.05). The relative contents of 132 bioactive compounds, especially p-hydroxyphenylacetic acid, citric acid, and dehydroepiandrosterone, were different between TSM-W and SISM-W. TSM-W:E had significantly higher 2,2-diphenyl-1-picrylhydroxy· (DPPH) scavenging and pancreatic lipase (PL) inhibitory activity than SISM-W:E (p < 0.05). DPPH scavenging and PL inhibitory activities were highly correlated with TFC and carbohydrates, respectively. Thus, bioactive compounds in P. brevitarsis extracts can be obtained selectively using pretreatment methods, which might be beneficial for high-value utilization of P. brevitarsis.

Synthesis of 17-Deacetoxyl Chromodorolide B Based on a Gold-Catalyzed Alkoxycyclization Reaction.

A novel strategy to construct the highly oxidized 3-oxabicyclo[3.3.0]octane skeleton was developed via a gold-catalyzed cascade cyclization with 2,7-dioxabicyclo[3.2.0]hept-3-ene as the substrate. We utilized this methodology as the key reaction to synthesize 17-deacetoxyl chromodorolide B.

Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor.

Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.

Essential Oil Bioactive Fibrous Membranes Prepared via Coaxial Electrospinning.

A novel antimicrobial composite material was prepared by encapsulating orange essential oil (OEO) in zein prolamine (ZP) via the coaxial electrospinning (ES) technique. By manipulating process parameters, the morphological features of ZP/OEO fibers were modulated. Fine fibers with diameters ranging from 0.7 to 2.3 µm were obtained by regulating ZP solution concentration and process parameters during the ES process. Optimal loading capacity (LC) and encapsulation efficiency (EE) of OEO in fibrous ZP mats were determined to be 22.28% and 53.68%, respectively, and were achieved using a 35 w/v% ZP ES solution. The encapsulation of OEO was found to be reliant on ZP solution concentration (the enveloping medium). SEM analysis indicates the surface morphology of ZP/OEO electrospun fibers is dependent on ZP solution loading volume, with lower ZP concentrations yielding defective fibrous structures (for example, beaded and spindled-string like morphologies). Furthermore, this loading volume also influences OEO LC, EE, mat water contact angle and oil retention. CCK-8 assay and cell morphology assessment (HEK293T cells) indicate no significant change with electrospun ZP and ZP/OEO fibrous membranes over an 8 h period. Antimicrobial activity assessment using Escherichia coli, suggests composite nonwovens possess sterilization properties; elucidating potential application in active food packaging, food preservation and therefore sustainability.

Total synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units.

Carbohydrates are diverse bio-macromolecules with highly complex structures that are involved in numerous biological processes. Well-defined carbohydrates obtained by chemical synthesis are essential to the understanding of their functions. However, synthesis of carbohydrates is greatly hampered by its insufficient efficiency. So far, assembly of long carbohydrate chains remains one of the most challenging tasks for synthetic chemists. Here we describe a highly efficient assembly of a 92-mer polysaccharide by the preactivation-based one-pot glycosylation protocol. Several linear and branched oligosaccharide/polysaccharide fragments ranging from 5-mer to 31-mer in length have been rapidly constructed in one-pot manner, which enables the first total synthesis of a biologically important mycobacterial arabinogalactan through a highly convergent [31+31+30] coupling reaction. Our results show that the preactivation-based one-pot glycosylation protocol may provide access to the construction of long and complicated carbohydrate chains.

Membrane fouling and anti-fouling strategies using RO retentate from a municipal water recycling plant as the feed for osmotic power generation.

RO retentate from a municipal water recycling plant is considered as a potential feed stream for osmotic power generation in this paper. The feasibility of using RO retentate from a municipal water recycling plant was examined from two aspects: (a) the membrane fouling propensity of RO retentate, and (b) the efficacy of anti-fouling strategies. The membranes used in this study were the inner selective thin film composite polyethersulfone (TFC/PES) hollow fiber membranes, which possessed a high water permeability and good mechanical strength. Scaling by phosphate salts was found to be one possible inorganic fouling on the innermost layer of the PES membrane, whereas silica fouling was observed to be the governing fouling on the outmost surface of the PES membrane. Two anti-fouling pretreatments, i.e., pH adjustment and anti-scalant pre-treatment for the feed stream, were studied and found to be straightforward and effective. Using RO retentate at pH 7.2 as the feed and 1 M NaCl as the draw solution, the average power density was 7.3 W/m(2) at 20 bar. The average power density increased to 12.6 W/m(2) by modifying RO retentate with an initial pH value of 5.5 using HCl and to 13.4 W/m(2) by adding 1.1 mM ethylenediaminetetraacetic acid (EDTA). Moreover, the flux recovery of the fouled membranes, without the indicated pretreatments, reached 84.9% using deionized (DI) water flushing and 95.0% using air bubbling under a high crossflow velocity of 23.3 cm/s (Re = 2497) for 30 min. After pretreatment by pH adjustment, the flux recovery increased to 94.6% by DI water flushing and 100.0% by air bubbling. After pretreatment by adding 1.1 mM EDTA into RO retentate, flux was almost fully restored by physical cleaning by DI water flushing and air bubbling. These results provide insight into developing an effective pretreatment by either pH adjustment or EDTA addition before PRO and physical cleaning methods by DI water flushing and air bubbling for membrane used in osmotic power generation.

Gypsum (CaSO4·2H2O) Scaling on Polybenzimidazole and Cellulose Acetate Hollow Fiber Membranes under Forward Osmosis.

We have examined the gypsum (CaSO4·2H2O) scaling phenomena on membranes with different physicochemical properties in forward osmosis (FO) processes. Three hollow fiber membranes made of (1) cellulose acetate (CA), (2) polybenzimidazole (PBI)/polyethersulfone (PES) and (3) PBI-polyhedral oligomeric silsesquioxane (POSS)/polyacrylonitrile (PAN) were studied. For the first time in FO processes, we have found that surface ionic interactions dominate gypsum scaling on the membrane surface. A 70% flux reduction was observed on negatively charged CA and PBI membrane surfaces, due to strong attractive forces. The PBI membrane surface also showed a slightly positive charge at a low pH value of 3 and exhibited a 30% flux reduction. The atomic force microscopy (AFM) force measurements confirmed a strong repulsive force between gypsum and PBI at a pH value of 3. The newly developed PBI-POSS/PAN membrane had ridge morphology and a contact angle of 51.42° ± 14.85° after the addition of hydrophilic POSS nanoparticles and 3 min thermal treatment at 95 °C. Minimal scaling and an only 1.3% flux reduction were observed at a pH value of 3. Such a ridge structure may reduce scaling by not providing a locally flat surface to the crystallite at a pH value of 3; thus, gypsum would be easily washed away from the surface.

[Expression of SOX4 gene and early recurrence of hepatocellular carcinoma: their relationship and the clinical significance].

OBJECTIVE: T To explore the relationship between the expression of SOX4 gene and early recurrence of hepatocellular carcinoma (HCC) after curative resection. METHODS: SOX4 expression was detected immunohistochemically in 60 HCC patients including 30 with and 30 without early recurrence after curative resection, with 30 normal liver specimens as the control. RESULTS: The expression of SOX4 was significantly higher in HCC than in normal liver (41.7% vs 16.7%, P<0.05), and in HCC tissues, the expression was significantly higher in early recurrent HCC after curative resection than in HCC without early recurrence (56.7% vs 26.7%, P<0.05). SOX4 expression was inversely correlated to the patients' gender, age, tumor size, HBsAg, and Edmonson grade (P<0.05). CONCLUSION: SOX4 is closely associated with early recurrence of HCC after curative resection, and its overexpression may contribute to early recurrence of HCC. SOX4 may serve as a new molecular indicator for evaluating the prognosis of HCC.