Development of New Thiophene-Containing Triaryl Pyrazoline Derivatives as PI3Kγ Inhibitors

A series of new thiophene-containing triaryl pyrazoline derivatives, 3a–3t, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of the tested compounds indicated potent PI3K inhibitory potency, with this series of compounds showing more potency for PI3Kγ than PI3Kα. The top hit 3s seemed more potent than the positive control LY294002 on inhibiting PI3Kγ (IC₅₀ values: 0.066 μM versus 0.777 μM) and more selective from PI3Kα (Index values: 645 versus 1.74). It could be inferred that the combination of para- and meta-, as well as the modification of the electron-donating moieties, led to the improvement in potency. The anti-proliferation inhibitory activity and the enzymatic inhibition potency indicated consistent tendencies. The top hit 3s could inhibit the phosphorylation of Akt by inhibiting PI3K through the PI3K-Akt-mTOR pathway. The molecular docking simulation indicated that the binding pattern of 3s into PI3Kγ was preferable than that of PI3Kα, with more hydrogen bond, more π-involved interactions, and fewer π-sulfur interactions. The information in this work is referable for the further development of selective inhibitors for specific isoforms of PI3K.     

Exogenous Melatonin Activating Nuclear Factor E2-Related Factor 2 (Nrf2) Pathway via Melatonin Receptor to Reduce Oxidative Stress and Apoptosis in Antler Mesenchymal Stem Cells

Antler growth depends on the proliferation and differentiation of mesenchymal stem cells (MSCs), and this process may be adversely affected by oxidative stress. Melatonin (MLT) has antioxidant functions, but its role in Cervidae remains largely unknown. In this article, flow cytometry, reactive oxygen species (ROS) identification, qPCR, and other methods were used to investigate the protective mechanism of MLT in H₂O₂-induced oxidative stress of antler MSCs. The results showed that MLT significantly increases cell viability by relieving the oxidative stress of antler MSCs. MLT inhibits cell apoptosis by protecting mitochondrial function. We blocked the melatonin receptor with luzindole (Luz) and found that the receptor blockade significantly increases H₂O₂-induced hyperoxide levels and causes significant inhibition of mitochondrial function. MLT treatment activates the nuclear factor E2-related factor 2 (Nrf2) antioxidant signaling pathway, up-regulates the expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and other genes and it could inhibit apoptosis. In contrast, the melatonin receptor blockade down-regulates the expression of Nrf2 pathway-related genes, but significantly up-regulates the expression of apoptotic genes. It was indicated that MLT activates the Nrf2 pathway through the melatonin receptor and alleviates H₂O₂-induced oxidative stress and apoptosis in antler MSCs. This study provides a theoretical basis for further studying the oxidative stress and antioxidant process of antler MSCs and, thereby, increasing antler yields.     

Identification and Characterization of a Novel Endo-β-1,4-Xylanase from Streptomyces sp. T7 and Its Application in Xylo-Oligosaccharide Production

A xylanase-producing strain, identified as Streptomyces sp. T7, was isolated from soil by our lab. The endo-β-1,4-xylanase (xynST7) gene was found in the genome sequence of strain T7, which was cloned and expressed in Escherichia coli. XynST7 belonged to the glycoside hydrolase family 10, with a molecular mass of approximately 47 kDa. The optimum pH and temperature of XynST7 were pH 6.0 and 60 °C, respectively, and it showed wide pH and temperature adaptability and stability, retaining more than half of its enzyme activity between pH 5.0 and 11.0 below 80 °C. XynST7 showed only endo-β-1,4-xylanase activity without cellulase- or β-xylosidase activity, and it showed maximal hydrolysis for corncob xylan in all the test substrates. Then, XynST7 was used for the production of xylo-oligosaccharides (XOSs) by hydrolyzing xylan extracted from raw corncobs. The maximum yield of the XOS was 8.61 ± 0.13 mg/mL using 15 U/mL of XynST7 and 1.5% corncob xylan after 10 h of incubation at 60 °C. The resulting hydrolysate products mainly consisted of xylobiose and xylotriose. These data indicated that XynST7 might by a promising tool for various industrial applications.     

Stereodivergent synthesis of enantioenriched azepino[3,4,5-cd]-indoles via cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel–Crafts reaction

The development of enantioselective annulation reactions using readily available substrates for the construction of structurally and stereochemically diverse heterocycles is a compelling topic in diversity-oriented synthesis. Herein, we report efficient catalytic asymmetric formal 1,3-dipolar (3 + 4) cycloadditions of azomethine ylides with 4-indolyl allylic carbonates for the construction of azepino[3,4,5-cd]-indoles fused with a challenging seven-membered N-heterocycle, a frequently occurring tricyclic indole scaffold in bioactive compounds and pharmaceuticals. Through cooperative Cu/Ir-catalyzed asymmetric allylic alkylation followed by intramolecular Friedel–Crafts reaction, an array of azepino[3,4,5-cd]-indoles were obtained in good yields with excellent diastereo-/enantioselective control. More importantly, the full stereodivergence of this transformation was established via synergistic catalysis followed by acid-promoted epimerization, and up to eight stereoisomers of the cycloadducts bearing three stereogenic centers could be predictably achieved from the same set of starting materials for the first time. Quantum mechanical computations established a plausible mechanism for the synergistic Cu/Ir catalysis to stereodivergently introduce two vicinal stereocenters whose stereochemical information is remotely delivered across the fused azepine ring to control the third chiral center. Epimerization of the last center involves protonation-enabled reversal of the thermodynamically controlled relative configuration.

A stereodivergent synthesis of azepino[3,4,5-cd]-indoles bearing three stereogenic centers was established via synergistic dual-metal catalysis followed by acid-promoted epimerization, and up to all eight stereoisomers could be predictably achieved.     

Five New Polyoxypregnane Glycosides from the Vines of Aspidopterys obcordata and Their Antinephrolithiasis Activity

From the dried vines of Aspidopterys obcordata Hemsl, five new polyoxypregnane glycosides, named obcordatas J–N (1–5), were obtained. Their structures were fully elucidated and characterized by HRESIMS and extensive spectroscopic data. In addition, all of the new compounds were screened for their antinephrolithiasis activity in vitro. The results showed that compounds 1–3 have prominent protective effects on calcium oxalate crystal-induced human kidney 2 (HK-2) cells, with EC₅₀ values ranging from 6.72 to 14.00 μM, which is consistent with the application value of A. obcordata in folk medicine for kidney stones.     

Hyperacmosin R,a New Decarbonyl Prenylphloroglucinol with Unusual Spiroketal Subunit from Hypericum acmosepalum

Two previously undescribed polycyclic polyprenylated acylphloroglucinols, hyperacmosins R-S (1–2), were obtained from the aerial parts of Hypericum acmosepalum. Their structures were elucidated by extensive spectroscopic analysis and electronic circular dichroism calculation (ECD). Compound 1 featured an unprecedented 5,8-spiroketal subunit as well as the loss of C-2′ carbonyl in the phloroglucinol ring. In addition, compounds 1 and 4 showed weak hepatoprotective activity against paracetamol-induced HepG2 cell damage at 10 μm. The plausible biosynthetic pathway of 1 was proposed via a retro-Clasisen reaction and decarboxylation.     

Triel Bond Formed by Malondialdehyde and Its Influence on the Intramolecular H-Bond and Proton Transfer

Malondialdehyde (MDA) engages in a triel bond (TrB) with TrX₃ (Tr = B and Al; X = H, F, Cl, and Br) in three modes, in which the hydroxyl O, carbonyl O, and central carbon atoms of MDA act as the electron donors, respectively. A H···X secondary interaction coexists with the TrB in the former two types of complexes. The carbonyl O forms a stronger TrB than the hydroxyl O, and both of them are better electron donors than the central carbon atom. The TrB formed by the hydroxyl O enhances the intramolecular H-bond in MDA and thus promotes proton transfer in MDA-BX₃ (X = Cl and Br) and MDA-AlX₃ (X = halogen), while a weakening H-bond and the inhibition of proton transfer are caused by the TrB formed by the carbonyl O. The TrB formed by the central carbon atom imposes little influence on the H-bond. The BH₂ substitution on the central C-H bond can also realise the proton transfer in the triel-bonded complexes between the hydroxyl O and TrH₃ (Tr = B and Al).     

Calculation of the anharmonic effect on the main reactions referring to ethylbenzene combustion mechanism

About 11 reactions related to ethylbenzene are studied in this paper using transition state theory. The YL method proposed by Yao and Lin is utilized to calculate the anharmonic and the harmonic rate constants in these reaction processes in the temperature range of 300–4,000 K, energy diagram and the temperature dependence of the rate coefficients are also presented. The calculations indicate that the harmonic rate constants are larger than the anharmonic rate constants in most cases. Especially, there is a temperature junction between the high and low relationship between the anharmonic and harmonic rate constants in several reactions. Furthermore, the calculated values are in good agreement with other theoretical ones within the allowable error. Finally, the kinetic parameters and the thermodynamic parameters are calculated. To sum up, it can be concluded that the anharmonic effect in these reactions is very significant and cannot be ignored.     

Biodegradable Sodium Alginate/Carrageenan/Cellulose Composite Hydrogel Wound Dressings Containing Herbal Extracts for Promoting Blood Coagulation and Wound Healing

Accelerating the coagulation process and preventing wound infection are major challenges in the wound care process. Therefore, new multifunctional wound dressings with procoagulant, antibacterial, and antioxidant properties have enormous potential for clinical application. In this work, biodegradable hydrogels containing herbal extracts are prepared for wound dressings. First, the active ingredients are extracted from Amaranthus spinosus (A. spinosus) and Rubia cordifolia (R. cordifolia) and added to the hydrogels prepared from microcrystalline cellulose (MCC), carrageenan, and sodium alginate. Then the composite hydrogels are air-dried to obtain the wound dressings. The wound dressings prepared in this work have good biocompatibility and moisture retention. The mechanical properties of the wound dressings are further improved with the addition of MCC. Besides, the wound dressings have excellent procoagulant, antibacterial, and antioxidant properties due to the presence of R. cordifolia extract. Overall, the most effective group of wound dressings with different ingredient formulations reduces clotting time by 75% and largely inhibits bacterial growth. The wound dressings perform well in the animal wound models to promote wound healing. These results indicate that the hydrogel wound dressings prepared in this work have great potential for medical applications.     

Photo-Activated Circularly Polarized Luminescence Film Based on Aggregation-Induced Emission Copper(I) Cluster-Assembled Materials

In this study, a pair of chiral copper(I) cluster-assembled materials (R/S- 2 ) was prepared, exhibiting unique photo-response characteristics with a concentration-wavelength correlation property in DMSO solution. By the combination of R/S- 2 with a polymethyl methacrylate (PMMA) matrix, the first photo-activated circularly polarized luminescence (CPL) film was developed, the CPL signal (g_lum=9×10⁻³) of which could be induced by UV light irradiation. Moreover, the film exhibited a reversible photo-response and extremely good fatigue resistance. Mechanism study revealed that the photo-response properties of the R/S- 2 solution and film are attributed to the aggregation-induced emission (AIE) characteristics of R/S- 2 and a photo-induced deoxygenation process. This study enriches the types of luminescent cluster-assembled molecules and provides a new strategy for the construction of metal cluster-based stimuli-responsive composite materials.