Metal-free iodination of arylaldehydes for total synthesis of aristogins A-F and hernandial.

Iodine is one of the most effective sources for iodination of aromatic compounds; however, its electrophilicity is insufficient for direct iodination. The selection of appropriate environmentally friendly and cost-effective oxidants in combination with iodine for the iodination of aromatic rings, along with its application in the synthesis of natural products, holds significant importance. A highly efficient method utilizing I(III) as the initiator has been successfully developed for monoiodination of arylaldehydes. The method demonstrates good compatibility with a wide range of (hetero)aromatic aldehydes, resulting in moderate to excellent yields, without the need for any toxic, volatile or explosive reagents. The synthesis of seven natural products, namely aristogins A-F and hernandial, was achieved through this iodination followed by Ullmann-type coupling.

α-Acyloxylation of Ketones/Cyclic Ethers Mediated by Hypervalent Iodine(III) Reagents as Oxidants and Nucleophilic Sources.

This study describes a catalyst-free α-acyloxylation of ketones and a KBr-mediated α-acyloxylation of cyclic ethers. These conversions are effectively mediated by hypervalent iodine(III) reagents serving dual roles as the oxidant and nucleophilic source. Consequently, esters are produced directly in moderate to excellent yields. The proposed method features good functional group compatibility, a broad substrate scope, and high synthetic efficiency and is remarkably environmentally friendly.

Discovery and Anti-Inflammatory Activity Evaluation of a Novel CDK8 Inhibitor through Upregulation of IL-10 for the Treatment of Inflammatory Bowel Disease In Vivo.

Increasing the anti-inflammatory cytokine interleukin-10 (IL-10) level is a promising strategy to suppress the progression of pathogenic inflammation including inflammatory bowel disease (IBD). Since cyclin-dependent kinase 8 (CDK8) inhibition can upregulate IL-10 abundance in activated myeloid-derived dendritic cells, it is considered to be an effective target for IBD treatment. Here, the complete discovery process of a novel CDK8 inhibitor as an anti-inflammatory agent was described. Starting with wogonin, structure-based optimization and structure-activity relationship (SAR) study were comprehensively carried out, and then lead compound 85 (N-(2-ethylphenyl)-5-(4-(piperazine-1-carbonyl)phenyl)nicotinamide) was developed as a potent druglike CDK8 inhibitor upregulating IL-10 both in vivo and in vitro. Also, compound 85 (with CDK8 IC50 = 56 nM, IL-10 enhancement rate 88%) exhibited effective anti-inflammatory activity in an animal model of IBD. These results confirmed that certain CDK8 inhibitor could be used as an effective anti-IBD drug.

Non-peptidyl non-covalent cathepsin C inhibitoEEr bearing a unique thiophene-substituted pyridine: Design, structure-activity relationship and anti-inflammatory activity in vivo.

Cathepsin C (Cat C) is involved in inflammation regulation by activating neutrophil serine proteases (NSPs). Therefore, Cat C is an attractive target for treatment of inflammatory diseases mediated by NSPs overactivation. In previous study, compounds 54 and 77 were reported to be the first non-peptidyl non-covalent Cat C inhibitors, with good enzyme inhibitory activity and NSPs activation inhibition, but their pharmacokinetic (PK) properties were unsatisfactory. In this study, starting from 77, after several rounds of structure-based design and modification, compound SF38, a novel Cat C inhibitor bearing a unique thiophene structure was identified, which exhibited strong inhibitory activity against Cat C (IC50 = 59.9 nM). Further mechanism study and in vivo evaluation showed that SF38 inhibited the Cat C activity in bone marrow and blood, decreased the activation of NSPs, and exhibited anti-inflammatory activity in an animal model of acute lung injury, with acceptable PK properties (F = 42.07%). These results enriched the structure-activity relationship (SAR) of Cat C inhibitor with thiophene structure characteristic, and proved the broad prospect of non-peptidyl non-covalent Cat C inhibitor.

Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor.

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.

Iodine(III) promotes cross-dehydrogenative coupling of N-hydroxyphthalimide and unactivated C(sp3)-H bonds.

Cross-dehydrogenative coupling reactions provide a method to construct new chemical bonds by direct C-H activation without any pre-functionalization. Compared to functionalization of a C-H bond α- to ether oxygen, α- to carbonyl, or at a benzylic position, functionalization of unactivated hydrocarbons is difficult and often requires high temperatures, a transition-metal catalyst, or a superstoichiometric quantity of volatile, toxic, and explosive tert-butylhydroperoxide. Here, a cross-dehydrogenative C-O coupling reaction of N-hydroxyphthalimide with unactivated alkanes, nitriles, ethers, and thioethers has been realized by using iodobenzene diacetate as the radical initiator. The current protocol enables efficient functionalization of unactivated hydrocarbons and nitriles through inert C(sp3)-H bond activation under mild reaction conditions. O-substituted NHPI derivatives are generated in good yields under metal-free conditions.

Source apportionment of fine organic carbon (OC) using receptor modelling at a rural site of Beijing: Insight into seasonal and diurnal variation of source contributions.

This study was designed to investigate the seasonal characteristics and apportion the sources of organic carbon during non-haze days (<75 µg m-3) and haze (≥75 µg m-3) events at Pinggu, a rural Beijing site. Time-resolved concentrations of carbonaceous aerosols and organic molecular tracers were measured during the winter of 2016 and summer 2017, and a Chemical Mass Balance (CMB) model was applied to estimate the average source contributions. The concentration of OC in winter is comparable with previous studies, but relatively low during the summer. The CMB model apportioned seven separate primary sources, which explained on average 73.8% on haze days and 81.2% on non-haze days of the organic carbon in winter, including vegetative detritus, biomass burning, gasoline vehicles, diesel vehicles, industrial coal combustion, residential coal combustion and cooking. A slightly lower percentage of OC was apportioned in the summer campaign with 64.5% and 78.7% accounted for. The other unapportioned OC is considered to consist of secondary organic carbon (SOC). During haze episodes in winter, coal combustion and SOC were the dominant sources of organic carbon with 23.3% and 26.2%, respectively, followed by biomass burning emissions (20%), whereas in summer, industrial coal combustion and SOC were important contributors. Diurnal contribution cycles for coal combustion and biomass burning OC showed a peak at 6-9 pm, suggesting domestic heating and cooking were the main sources of organic aerosols in this rural area. Backward trajectory analysis showed that high OC concentrations were measured when the air mass was from the south, suggesting that the organic aerosols in Pinggu were affected by both local emissions and regional transport from central Beijing and Hebei province during haze episodes. The source apportionment by CMB is compared with the results of a Positive Matrix Factorization (PMF) analysis of ACSM data for non-refractory PM1, showing generally good agreement.

A novel lignin degradation bacteria-Bacillus amyloliquefaciens SL-7 used to degrade straw lignin efficiently.

Using tobacco straw (Ts) and lignin as the sole carbon source, a strain was isolated from Ts and identified as Bacillus amyloliquefaciens SL-7 by 16S rDNA gene-sequencing technology.7-day incubation of Bacillus amyloliquefaciens SL-7 can reduce the chemical oxygen demand (COD) by 69.35% in lignin mineral salt medium. The activity of Manganese peroxidase (MnP) reached maximum level 258.57 U L-1, and Lignin peroxidase (Lip) was 422.68 U L-1 at 4th day. The highest Laccase (Lac) activity (55.95 U L-1) was observed at 3th day. After straw-liquid fermentation degradation of 15 days, the bacterial could degrade 28.55% lignin of the straw which was close to that of fungi. Compared with the control group and effective microorganisms (EM) group, the lignin degradation rate in Bacillus amyloliquefaciens SL-7 group increased by 22.26% and 11.70% at 41-day compost fermentation of tobacco straw. These show the strain has strong lignin degradation performance.

Design, synthesis and anticancer activity of naphthoquinone derivatives.

Basis on molecular docking and pharmacophore analysis of naphthoquinone moiety, a total of 23 compounds were designed and synthesised. With the help of reverse targets searching, anti-cancer activity was preliminarily evaluated, most of them are effective against some tumour cells, especially compound 12: 1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl-4-oxo-4-((4-phenoxyphenyl)amino) butanoate whose IC50 against SGC-7901 was 4.1 ± 2.6 µM. Meanwhile the anticancer mechanism of compound 12 had been investigated by AnnexinV/PI staining, immunofluorescence, Western blot assay and molecular docking. The results indicated that this compound might induce cell apoptosis and cell autophagy through regulating the PI3K signal pathway.

Binding patterns and structure-activity relationship of CDK8 inhibitors.

A major goal of medicinal chemists is to identify and validate novel and effective kinase targets for treatment of cancer. Recent studies have shown that cyclin-dependent kinase 8 (CDK8) is a target for treatment of colorectal, breast, melanoma, and prostate cancers. The crystal structure of CDK8 has been reported, and eutectic interactions have been identified for 24 compounds that target CDK8. To more effectively develop CDK8 inhibitors, particularly those with improved selectivity, we summarized the structure, structure-activity relationships, and binding information of typical CDK8 inhibitors, which may serve as a reference for development of novel CDK8 inhibitors.

Binding Characteristics and Superimposed Antioxidant Properties of Caffeine Combined with Superoxide Dismutase.

The binding characteristics and superimposed antioxidant properties of caffeine combined with copper/zinc superoxide dismutase (SOD) were studied. The superimposed antioxidant activity of caffeine with SOD was investigated by detecting the concentration of malondialdehyde (MDA) present in cells, which was induced by hyperthermia and heavy metal exposure. The interactions between the SOD enzyme and caffeine were researched by ultraviolet spectrum, fluorescence spectrum, and molecular computation. The relative amounts of MDA contents of caffeine (0.1 mmol/L), SOD (0.1 mg/L), and caffeine (0.1 mmol/L) and SOD (0.1 mg/L) to water in cells were 0.70, 0.72, and 0.54, respectively, indicating that the antioxidant properties of caffeine combined with SOD may be superimposed. The fluorescence spectroscopy and molecular computation results show that the mixture of caffeine and SOD can result in the formation of a 1:1 complex through hydrogen bond and van der Waals forces spontaneously. The binding constant (K a) of caffeine with SOD at five different temperatures are 4.41 × 104, 3.30 × 104, 2.29 × 104, 1.71 × 104, and 1.17 × 104 L/mol. The changes of Gibbs-free energy (ΔG) are -26.50, -26.21, -25.71, -25.12, and -24.29 KJ/mol and the ΔG of molecular docking calculation is -26.95 KJ/mol. The experimental results are in accordance with the results of theoretical calculations. The combination of caffeine with SOD can change the conformation and microenvironment of SOD but does not change the activity of SOD. In addition, the combination can superimpose the antioxidant activity of caffeine and SOD.

Study on the interaction and antioxidant activity of theophylline and theobromine with SOD by spectra and calculation.

Theophylline (TP) and theobromine (TB) are the methyl derivatives of xanthine. The antioxidation of TP and TB as well as the effect of the antioxidation and activity of copper­zinc superoxide dismutase (SOD) with TP and TB were investigated. The contents of MDA in cells showed that both TP (14.49 µmol/g) and TB (14.25 µmol/g) are active in oxidation resistance and closed to the antioxidant effect of SOD (13.77 µmol/g). With the formation of TP-SOD and TB-SOD, the antioxidant ability can be superimposed. The interactions between TP/TB and SOD were studied by ultraviolet spectrum, fluorescence spectrum and molecular docking. The results showed that the complex of TP/TB and SOD with 1:1 component was stabilized by hydrogen bonding and van der Waals forces. The analysis also indicated that the microenvironment and structure of SOD were changed. All of the results indicate that the complex formation of TP-SOD and TB-SOD can maintain their respective antioxidant effects without changes in the activity of SOD.

Direct C-H bond arylation of (benzo)oxazoles with aryl chlorides catalyzed by N-heterocyclic carbene-palladium(II)-1-methylimidazole complex.

The direct C-H bond arylation of (benzo)oxazoles with aryl chlorides was achieved catalyzed by a well-defined NHC-Pd(II)-Im complex. Under the optimal conditions, various aryl chlorides were successfully applied as the arylating reagents to achieve the 2-aryl (benzo)oxazoles in acceptable to high yields, providing a convenient and alternative method for the direct C-H bond arylation of (benzo)oxazoles and enriching the chemistry of the NHC-Pd(II) complex in organic synthesis.

Proteomic identification, characterization and expression analysis of Ctenopharyngodon idella VDAC1 upregulated by grass carp reovirus infection.

Voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane are mitochondrial porins that play central roles in regulating cell life and death. In this present report, the VDAC protein 1 from grass carp Ctenopharyngodon idella (designated as CiVDAC1) was found to be upregulated by grass carp reovirus (GCRV) infection through two-dimensional gel electrophoresis and protein analysis of infected C. idella kidney (CIK) cells. The full-length cDNA of CiVDAC1 was 995 bp with an open reading frame (ORF) of 852 bp that encodes a putative 283-amino acid protein. Phylogenic analysis revealed that the complete ORF of CiVDAC1 demonstrated high identity with well characterized mammalian homologs. The deduced CiVDAC1 protein contains an α-helix at the amino terminal, 19 membrane-spanning ß-strands, and one eukaryotic mitochondrial porin signature motif. Tissue tropism analysis indicated that CiVDAC1 is abundant in muscle, heart, skin, swim bladder, trunk kidney and spleen. Transcriptional expression profiles indicated that the CiVDAC1 gene was upregulated upon viral challenge in a manner similar to the Mx2 gene, which is a marker gene used to indicate activation of innate antiviral immunity. Similar expression patterns of the CiVDAC1 gene were observed in CIK cells stimulated with poly (I:C), as well as grass carp kidney tissue challenged with GCRV in vivo. CiVDAC1 silencing in CIK cells had no impact on progeny virus production, but over-expression of CiVDAC1 in vivo showed strongly protect against challenge with live virus. To interpret the role of other VDAC proteins in viral pathogenesis, CiVDAC2 was characterized and showed to respond positively to GCRV challenge, which suggested that CiVDAC2 might functionally complement CiVDAC1 in C. idella. The present data did demonstrate that CiVDAC1 might be mediated grass carp antiviral immune response.

Lipopolysaccharide-induced TNF-α factor in grass carp (Ctenopharyngodon idella): evidence for its involvement in antiviral innate immunity.

Lipopolysaccharide-induced TNF-α factor (LITAF), which participates in innate immune response and regulates TNF-α transcription, has been identified and characterized in various organisms. In a study to screen interacting cellular proteins with grass carp reovirus using yeast two-hybrid system, a grass carp homologue of LITAF was identified to bind the NS26 protein encoded by the S11 genomic fragment of Grass carp reovirus (GCRV). In this study, grass carp LPS-induced TNF-α factor gene (designated as CiLITAF) was cloned and sequenced from the cDNA library constructed for the yeast two-hybrid screening. The CiLITAF cDNA contained an open reading frame (ORF) of 483 bp encoding a polypeptide of 161 amino acids with an estimated molecular mass of 17.0 kDa. In CIK cells infected with GCRV or treated with poly (I:C), transiently stimulated transcription of CiLITAF mRNA was noticed at 8 h post infection or poly (I:C) treatment. Grass carp TNF-α (CiTNFα) transcriptional level was also transiently induced to a high level following the stimulation of CiLITAF in these in vitro tests. In vivo analysis further showed that, significantly up-regulated transcriptional expression of both CiLITAF and CiTNFα were detected in the spleen tissue as early as 48 h post challenge with GCRV. This study thus characterized CiLITAF as an inducible gene responding to viral infection.