Photocatalysed C-H amidation of indoles enabled by tert-butyl alkyl((perfluoropyridin-4-yl)oxy)carbamate.

Development of a new catalytic and straightforward strategy to construct C-N bonds is playing a pivotal role in synthetic chemistry. Here, we report a photocatalysed protocol to access direct C-H amidation of indoles, enabled by a rationally designed tert-butyl alkyl((perfluoropyridin-4-yl)oxy)carbamate. A series of biologically important aminoindoles were prepared under mild conditions with excellent regioselectivity and broad substrate scope.

N-Chlorosulfonyl carbamate-enabled, photoinduced amidation of quinoxalin-2(1H)-ones.

Reported herein is the design and development of a new photo-induced amidation protocol with the readily available N-chlorosulfonyl carbamate as an effective amidyl-radical precursor, which could be readily prepared from commercial low-cost chlorosulfonyl isocyanate (CSI) and alcohol feedstocks. The synthetic potency of this developed protocol was well demonstrated by direct amidation of various quinoxalin-2(1H)-ones. The protocol could be further streamlined by implementing a one-pot/two-step/three-component process of CSI, alcohol, and quinoxalin-2(1H)-one, with significantly improved reaction efficiency. This methodology offers an intriguing opportunity for rapid expansion of nitrogen-containing molecular complexity, thus inspiring comprehensive exploration of a new reaction mode of CSI reagent.

Visible-light-driven oxidation of organosilanes by a charge-transfer complex.

Direct oxidation of organosilanes is one of the most straightforward ways to access silanols. Herein, we describe a novel photo-induced strategy for oxidation of organosilanes to access silanols, promoted by a photoactive charge-transfer complex (CTC) between sodium benzenesulfinate and molecular O2. A streamlined sequence transformation of organosilanes to silyl ethers was also readily achieved. This developed protocol represents the first example of CTC-based oxidation of organosilanes, offering a facile approach to access a series of silanol and silyl ether products.

Photochemical Organocatalytic Aerobic Cleavage of C═C Bonds Enabled by Charge-Transfer Complex Formation.

A novel visible-light-driven organocatalytic protocol to access aerobic oxidative cleavage of olefins, promoted by sodium benzene sulfinate, is described herein. An array of alkenes smoothly delivered the corresponding aldehydes and ketones under transition-metal-free conditions. Notably, α-halo-substituted styrenes proceeded with photoinduced oxidation to finally afford α-halo-acetophenones with halogen migration. Crucial to this oxidation was the formation of charge-transfer complexes between sodium benzene sulfinate with molecular O2 to ultimately deliver the carbonyl products.

Photoinduced Construction of a Benzothienopyridine-S,S-dioxide Framework Enabled by Polychloropyridyl Multifunctional Motifs.

Reported herein is a visible-light-induced, catalyst-free intramolecular cyclization of 4-phenylsulfonyl-2,3,5,6-tetrachloropyridine, leading to rapid assembly of a series of unprecedented benzo[4,5]thieno[3,2-c]pyridine 5,5-dioxide scaffolds under mild conditions. The rational introduction of a perchloropyridin-4-yl module significantly facilitated this photoinduced process and offers a versatile platform for broad structural variation. Mechanistic studies revealed that a newly identified charge-transfer complex with carbonate is crucial to this photoinduced process.

Augmenter of liver regeneration (ALR) regulates acute pancreatitis via inhibiting HMGB1/TLR4/NF-κB signaling pathway.

This research aimed to explore the effect of augmenter of liver regeneration (ALR) in acute pancreatitis (AP) of mice and the underlying mechanism. Caerulein were given to mice to get AP models. AP mice were given saline, ALR plasmids or negative control plasmids. Then, pancreas tissues were fixed and stained for histological examination. The levels of serum amylase, serum lipase, MPO, HMGB1, TNF-α, IL-1ß as well as MCP-1 were detected by ELISA assay. The mRNA levels of TLR4, p65, IκBα, iNOS, COX-2 and GAPDH were examined by RT-qPCR. The protein levels of HMGB1, TLR4, MD2, MyD88, IκBα and GAPDH were detected by western blotting. ALR decreased serum amylase as well as lipase levels and alleviated the histopathological alterations of the pancreas in AP mice. ALR decreased the MPO activity of pancreas in AP Mice. ALR decreased the HMGB1/TLR4 signaling pathway in AP Mice. ALR decreased pancreas IL-1ß and MCP-1 in AP mice, and also decreased plasma TNF-α and IL-1ß in AP mice. ALR attenuated the cerulein-caused increase in p65 mRNA and protein levels, but had no effects on mRNA and protein levels of IκBα. The AP mice significantly promoted the mRNA levels of iNOS and COX-2 that was inhibited by ALR. HNE formation was also increased in AP mice, but it was decreased by ALR. ALR alleviates acute pancreatitis by inhibiting HMGB1/TLR4/NF-κB signaling pathway. It is promising to alleviate the syndromes of patients with acute via targeting ALR.

The Toll-like receptor 4 antagonist TAK-242 protects against chronic pancreatitis in rats.

Chronic pancreatitis is a progressive disease characterized by irreversible morphological changes to the pancreas, typically causing pain and permanent loss of function. It is a poorly understood disease with the pathogenesis remaining unclear. The authors' previous data demonstrated that the inhibition of Toll­like receptor 4 (TLR4) using TLR4 antagonist kinase (TAK)­242 attenuates taurocholate­induced oxidative stress via the regulation of mitochondrial function in the pancreatic acinar cells of mice. In the present study, the effect of TAK­242 on trinitrobenzene sulfonic acid (TNBS)­induced chronic pancreatitis was investigated in rats. The results revealed that TAK­242 attenuated the severity of chronic pancreatic injury, and regulated extracellular matrix secretion and cellular immunity. In addition, TAK­242 treatment significantly decreased cell apoptosis, as evidenced by the reduction in Terminal deoxynucleotidyl transferase dUTP nick end labeling­positive cells in pancreas tissue sections, and also promoted cell proliferation in TNBS­treated animals. Furthermore, the results of the calibrated von Frey filament assay demonstrated that TAK­242 could prevent the pancreatitis­induced referred abdominal hypersensitivity. In summary, TAK­242 exhibits protective effects against TNBS­induced chronic pancreatitis and may be a potential therapeutic strategy for the treatment of patients with chronic pancreatitis.

PEGylated niosomes-mediated drug delivery systems for Paeonol: preparation, pharmacokinetics studies and synergistic anti-tumor effects with 5-FU.

This work describes the preparation of a PEGylated niosomes-mediated drug delivery systems for Paeonol, thereby improving the bioavailability and chemical stability of Paeonol, prolonging its cellular uptake and enhancing its synergistic anti-cancer effects with 5-Fu. PEGylated niosomes, which are prepared from biocompatible nonionic surfactant of Spans 60 and cholesterol, and modified with PEG-SA. Pae-PEG-NISVs were evaluated in vitro and in vivo. The cytotoxicity of Pae-PEG-NISVs was investigated against HepG2 cells. Fluorescence microscope was used to detect the apoptotic morphological changes. Growth inhibition assays were carried out to investigate whether Pae-PEG-NISVs could enhance the antiproliferative effects of Pae co-treated with 5-FU on HepG2 cells. The optimized Pae-PEG-NISVs had mean diameters of approximately 166 nm and entrapment efficiency (EE) of 61.8%. Furthermore, the in vitro release study of Paeonol from PEGylated niosomes exhibited a relatively prolonged release profile for 12 h. Pharmacokinetic studies in rats after i.v. injection showed that Pae-PEG-NISVs had increased elimination half-lives (t1/2, 87.5 versus 17.0 min) and increased area under the concentration-time curve (AUC0-t, 38.0 versus 19.48 µg/ml*min) compared to Paeonol solution. Formulated Paeonol had superior cytotoxicity versus the free drug with IC50 values of 22.47 and 85.16 µg/mL at 24 h on HepG2 cells, respectively, and we found that low concentration of Pae-PEG-NISVs and 5-Fu in conjunction had obviously synergistic effect. Our results indicate that the PEG-NISVs system has the potential to serve as an efficient carrier for Paeonol by effectively solubilizing, stabilizing and delivering the drug to the cancer cells.

The toll-like receptor 4 antagonist transforming growth factor-ß-activated kinase(TAK)-242 attenuates taurocholate-induced oxidative stress through regulating mitochondrial function in mice pancreatic acinar cells.

BACKGROUND: Acute pancreatitis (AP) is a commonly occurring and potentially life-threatening disease. Recently, toll-like receptor 4 (TLR4) has been considered as a new clue for studying the pathogenesis of AP due to its important role in inflammatory response cascade. MATERIALS AND METHODS: The aim of this study was to investigate the potential protective effect of transforming growth factor-ß-activated kinase (TAK)-242, a novel TLR4 antagonist, in taurocholate-treated mice pancreatic acinar cells. The protective effects were measured by cell viability, lactate dehydrogenase release and apoptosis, and oxidative stress was assayed by lipid peroxidation and oxidative enzyme activities. To determine the potential underlying mechanisms, mitochondrial cytochrome c release, swelling, and calcium buffering capacity were measured in isolated mitochondria, and mitochondrial biogenesis and expression of mitochondrial dynamic proteins were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: Treatment with 6-mM taurocholate significantly increased the expression of TLR4 at both mRNA and protein levels. TAK-242 markedly increased cell viability, decreased lactate dehydrogenase release, and inhibited apoptotic cell death as measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining in pancreatic acinar cells. These protective effects were accompanied by the suppressed lipid peroxidation and enhanced endogenous antioxidative enzyme activity. Using isolated and purified mitochondria from pancreatic acinar cells, we found that TAK-242 treatment also inhibited cytochrome c release into the cytoplasm, mitochondrial swelling, and decrease in mitochondrial Ca2+ buffering capacity after taurocholate exposure. In addition, TAK-242 significantly promoted mitochondrial biogenesis, as evidenced by increased mtDNA and upregulated mitochondrial transcription factors. The results of Western blot analysis showed that TAK-242 also differently regulated the expression of mitochondrial fusion and fission proteins. CONCLUSIONS: All these data strongly indicated that blocking TLR4 activity via TAK-242 exerts protective effects in an in vitro AP model, and it could be a possible strategy to improve clinical outcome in AP patients.

[Detecting the isoflurane in the air of workplaces with chromatographic method].

OBJECTIVE: To establish a solvent desorption Gas chromatographic method for detecting the isoflurane in air of workplaces. METHODS: This method is based on "Standardization of methods for determination of toxic substances in workplace air". RESULTS: This method presents the linear relation with the minimum detectable limit 1.0 µg/ml and the minimum detectable concentration 0.07 mg/m(3). The precision (RSD) was 0.5% ∼ 5.0%, the mean dsorption efficiencies were 96.7% ∼ 98.9%, the absorption efficiencies were 92.1% ∼ 100%, the breakthrough volume was 3.7 mg isoflurane/100 mg active carbon. Other volatile organic solvents (Sevoflurane, Enflurane and Ethyl Alcohol) did not interfere the detection. The sample could be stored in the active carbon tube at least for 10 days. CONCLUSION: This method is meet the requirement of GBZ/T 210.4-2008 "Guide for establishing occupational health standards-Part4: Determination methods of air chemicals in workplace" and is feasible for determining the isoflurane in the air of workplaces.

[Progress in the research of antizyme].

Antizyme is a small protein induced by elevated intracellular polyamines. Antizyme binds specifically to ornithine decarboxylase (ODC) , targeting ODC for ubiquitin-independent degradation by the 26S protosome, which consequently reduces polyamine synthesis. Polyamine transport may also be regulated by antizyme, through which the cellular polyamine levels are maintained. In recent years, more and more studies focus on antizyme with the development of biotechnique. In this article, advancements in the antizyme family, synthesis, function and intracellular location are reviewed.