Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors.

Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung cancer with the lowest IC50 value (0.09 µM < IC50 < 0.86 µM). Compared with CA-4, Compounds 8j and 8o displayed lower cytotoxicities toward normal cells but higher antiproliferative activities against RKO (IC50 = 0.15 µM and 0.09 µM respectively), NCI-H1299 (IC50 = 0.73 µM and 0.14 µM respectively), and A549 cells (IC50 = 0.86 µM and 0.37 µM respectively). Further investigations revealed that 8o shows higher tubulin polymerization inhibitory activity (IC50 = 3.1 ± 0.5 µM) than colchicine (IC50 = 8.6 ± 0.2 µM), and induced cell cycle arrest at the G2/M phase and cellular apoptosis through disrupting the microtubule network.

A novel electrochemical immunosensor based on Fe3O4@graphene nanocomposite modified glassy carbon electrode for rapid detection of Salmonella in milk.

Foods contaminated by foodborne pathogens have always been a great threat to human life. Herein, we constructed an electrochemical immunosensor for Salmonella detection by using a Fe3O4@graphene modified electrode. Because of the excellent electrical conductivity and mechanical stability of graphene and the large specific surface area of Fe3O4, the Fe3O4@graphene nanocomposite exhibits an excellent electrical signal, which greatly increased the sensitivity of the immunosensor. Gold nanoparticles were deposited on Fe3O4@graphene nanocomposite by electrochemical technology for the immobilization of the antibody. Cyclic voltammetry was selected to electrochemically characterize the construction process of immunosensors. The microstructure and morphology of related nanocomposites were analyzed by scanning electron microscopy. Under optimized experimental conditions, a good linear relationship was achieved in the Salmonella concentration range of 2.4 × 102 to 2.4 × 107 cfu/mL, and the limit of detection of the immunosensor was 2.4 × 102 cfu/mL. Additionally, the constructed immunosensor exhibited acceptable selectivity, reproducibility, and stability and provides a new reference for detecting pathogenic bacteria in milk.

A fluorescent biosensor based on quantum dot-labeled streptavidin and poly-l-lysine for the rapid detection of Salmonella in milk.

Salmonella, as a common foodborne pathogen in dairy products, poses a great threat to human health. We studied a new detection method based on quantum dots (QD). A fluorescent biosensor with multiple fluorescent signal amplification based on a streptavidin (SA) biotin system and the polyamino linear polymer poly-l-lysine (PLL) were established to detect Salmonella in milk. First, Salmonella was captured on a black 96-well plate with paired Salmonella mAb to form a double-antibody sandwich. Second, SA was immobilized on biotin-modified mAb by SA-biotin specific bond. Then, the biotin-modified polylysine (BT-PLL) was bound on SA and specifically bonded again through the SA-biotin system. Finally, water-soluble CdSe/ZnS QD-labeled SA was added to a black 96-well plate for covalent coupling with BT-PLL. The fluorescent signal was amplified in a dendritic manner by the layer-by-layer overlap of SA and biotin and the covalent coupling of biotinylated PLL. Under optimal conditions, the detection limit was 4.9 × 103 cfu/mL in PBS. The detection limit was 10 times better than that of the conventional sandwich ELISA. In addition, the proposed biosensor was well specific and could be used for detecting Salmonella in milk samples.

Meyer-Schuster-Type Rearrangement of Propargylic Alcohols into α-Selenoenals and -enones with Diselenides.

We describe a mild and broadly applicable protocol for the preparation of a diverse array of multisubstituted α-selenoenals and -enones from readily accessible propargylic alcohols and diselenides. The transformation proceeds via the Selectfluor-promoted selenirenium pathway, which enables selenenylation/rearrangement of a variety of propargylic alcohols. Gram-scale experiments showed the potential of this synergistic protocol for practical application.

Rapid detection of Salmonella in milk with a nuclear magnetic resonance biosensor based on a streptavidin-biotin system and a polyamidoamine-dendrimer-targeted gadolinium probe.

Rapid and sensitive detection technology is the key to preventing food-borne disease outbreaks. In this study, a low-field nuclear magnetic resonance (NMR) biosensor based on polyamidoamine dendrimers was prepared for the rapid detection of Salmonella in milk. The polyamidoamine dendrimer was biotinylated by amide reaction and chelated to diethylene triamine pentacetate acid and gadolinium to form magnetic complexes. The antibody and magnetic complexes were combined through a streptavidin-biotin system using streptavidin as an intermediate bridge to obtain the immunoprobe. Salmonella was captured by the immunoprobe via antigen-antibody interaction and then separated from the mixture by membrane filtration. Finally, the longitudinal relaxation signal of the filtrate was obtained by NMR. The biosensor had excellent anti-interference capability and could detect Salmonella within 1.5 h at a sensitivity of 103 cfu mL-1. This method based on NMR can realize detection in complex samples and has the potential to be a quick and nondestructive method for detecting target bacteria.

Rapid detection of Salmonella in milk by a nuclear magnetic resonance biosensor based on the streptavidin-biotin system and O-carboxymethyl chitosan target gadolinium probe.

Rapid and sensitive detection of foodborne pathogens is of great importance for food safety. Here, a set of nuclear magnetic resonance (NMR) biosensors based on a O-carboxymethyl chitosan target gadolinium (Gd) probe was developed to quickly detect Salmonella in milk by combining NMR technology and bioimmunotechnology with membrane filtration technology. First, O-carboxymethyl chitosan (O-CMC) was biotinylated to prepare biotinylated O-carboxymethyl chitosan (biotin-O-CMC) through amide reaction, and biotinylated magnetic complexes (biotin-O-CMC-Gd) were obtained by using O-CMC, which has strong chelating adsorption on Gd. The target probe was obtained by combining biotin-O-CMC-Gd with the biotinylated antibody (biotin-antibody) via streptavidin (SA) by introducing the SA-biotin system. Then, Salmonella was captured by the target probe through antigen-antibody interaction. Finally, NMR was used to measure the longitudinal relaxation time (T1) of the filtrate collected by membrane filtration. This NMR biosensor with good specificity and high efficiency can detect Salmonella with the sensitivity of 1.8 × 103 cfu/mL within 2 h; in addition, it can realize the detection of complex samples because of its strong anti-interference capability and may open up a new method for rapid detection of Salmonella, which has a great application potential.

Hydrogen Production from Formic Acid by In Situ Generated Ni/CdS Photocatalytic System under Visible Light Irradiation.

Simple and practical noble-metal-free catalyzed hydrogen production from sustainable resources, such as renewable formic acid, is highly desirable. Herein, the development of an efficient photocatalytic hydrogen production from aqueous solution of formic acid using in situ generated Ni/CdS photocatalytic system was described. CdS-Cys (Cys=l-cysteine) quantum dots (QDs) acting as photocatalyst with Ni(OAc)2 as H2 production catalyst precursor, a 94 % yield was obtained within 5 h under visible light irradiation at 50 °C. The average rate of H2 production reached up to 282 µmol mg-1 h-1 with 99.8 % H2 selectivity. Mechanistic studies indicate cooperation of dynamic quenching and static quenching of CdS-Cys QDs by Ni(OAc)2 . Especially, Ni0 , generated in the dynamic quenching, accelerated the electron transfer by acting as an electron outlet and enhancing the stability of CdS to slow down the photocorrosion distinctly, delivering efficient H2 production with high selectivity. Our study will inspire exploration of various efficient non-noble-metal catalysts for practical H2 production from bio-based formic acid.

Rheological Properties and Early-Age Microstructure of Cement Pastes with Limestone Powder, Redispersible Polymer Powder and Cellulose Ether.

In order to study the synergistic effects of organic and inorganic thickening agents on the rheological properties of cement paste, the rheological parameters, thixotropy cement-paste containing limestone powder (LP), re-dispersible polymer powder (RPP), and hydroxypropyl methylcellulose ether (HPMC) were investigated using the Anton Paar MCR 102 rheometer at different resting times. The early-age hydration process, hydration products, and microstructure were also analyzed with scanning electron microscopy (SEM) and thermogravimetry analyses (TGA). The results showed that the addition of LP, RPP, and HPMC affected the rheological properties of cement paste, but the thickening mechanism between organic and inorganic thickening agents was different. The small amount of LP increased the plastic viscosity but decreased the yield stress of cement paste due to its dense filling effect. Adding 1% of RPP improved the thixotropic property of cement paste by 50%; prolonging the standing time could improve the thixotropic performance by as much as two times. Only 0.035% HPMC added to the cement paste increased the plastic viscosity by 20%, while the yield stress increased nearly twice. The more HPMC added, the more significant effect it showed. Cement paste compounds with LP, RPP, and HPMC balanced the yield stress and plastic viscosity and improved the thixotropy. The C-L6-R1.0-H0.035 paste presented as a pseudoplastic, its rheological indexes were close to one, and it was hardly affected by the resting time. The composite superposition effect of organic and inorganic thickening agents reduced the impact of resting time for all pastes. As the organic thickening component inhibited the hydration more than the LP promoted the hydration of the cement paste, indicating that the C-L6-R1.0-H0.035 paste remained in the particle fusion stage after curing for three days, as shown by the SEM images.

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease.

Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 µM) and PDE4D (IC50 = 1.88 µM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent anti-neuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.

Discovery of Novel 3-Amino-4-alkoxyphenylketones as PDE4 Inhibitors with Improved Oral Bioavailability and Safety against Spatial Memory Impairments.

To realize PDE4 inhibitors with good developmental potentiality for the treatment of dementia, structure-based optimizations of lead compound FCPR03 resulted in novel aminophenylketones 9c and 9H with low nanomolar potency, which displayed comparable activity to rolipram, satisfactory bioavailability (F% = 36.92 and 42.96% respectively), and good blood-brain barrier (BBB) permeability switching from the cyclopropyl methoxy group to the cyclopropyl methylamine and the amide group to the corresponding ketone. Emetogenicity evaluation on a combined ketamine/xylazine anesthesia mice alternative model demonstrated that 9H displays no emetogenicity even at an oral dose of 5 mg/kg. In contrast, rolipram and roflumilast displayed emetogenicity at an oral dose of 0.5 mg/kg. In acute toxicological evaluation, 9H showed no obvious toxicological effect on mice when administered at oral doses below 625 mg/kg. Further investigations revealed that 9H improves the memory and cognitive impairment of Alzheimer's disease (AD) model mice induced by Aß25-35.

[Spatiotemporal Differentiation and Degradation Analysis of Polybrominated Diphenyl Ethers in Sediments of Shanmei Reservoir and Its Inflowing River, Quanzhou, China].

To investigate the spatiotemporal differentiation of polybrominated diphenyl ethers (PBDEs) in urban water-source reservoirs and degradation sources of BDE homologues and their contributions, we analyzed the contents, pollution degrees, spatial distributions, hydrological period changes, inventories, profiles, and degradation source contributions of PBDEs in the surface sediments of Shanmei Reservoir and its inflowing river, Quanzhou, China. The results showed that the median ∑PBDEs (1072.1 ng ·g-1) in the inflowing river sediment was 6.7 times than that of the reservoir (160.4 ng ·g-1) and the total amount of ∑PBDEs in sediments per unit area (80.3 kg ·km-2) was 6.3 times than that of Taihu Lake and 188 times than that of the Great Lakes in North America. The pollution degrees of PBDEs in Shanmei Reservoir were more severe than those of most lakes and reservoirs at home and abroad, which was dominated by BDE-209 (84.5%-99.2%). Most of the sampling sites in the reservoir (r 0.564-0.994, P<0.034) and the inflowing river (r 0.953-1.0, P<0.000) had high similarity in the composition of PBDEs. Significantly positive correlations (r 0.779-0.964, P<0.005) were observed between the reservoir entry area and river sampling sites, which were stronger than the other functional areas, indicating that the inflowing river was a major pollution source of PBDEs in the Shanmei Reservoir. The tail region of the reservoir had low correlations with the inflowing river (r 0.454-0.915, P≤0.128), and was relatively much more affected by Jiudu Town. The changes in hydrological period of the ∑PBDEs were relatively consistent at each sampling site (r 0.617-0.714, P≤0.077), but the impact of the changes in the hydrological period on the ∑PBDEs was not statistically significant (P=0.178, Two-Way ANOVA). However, the site changes had a significant influence on the ∑PBDEs (P=0.0001), and significant or nearly differences were observed between the reservoir entry area and other functional areas (P 0.019-0.061), indicating that the spatial distribution variations of the PBDEs in reservoir sediments were greater than the changes in hydrological period. The natural degradation of the PBDEs gradually increased from the river to the reservoir entry area and then to the central reservoir area. The reductive debromination rates varied at different brominated levels, and some BDE homologues accumulated due to their slowly continued degradation velocities. Research on abundance ratios indicated that the lower brominated BDE homologues were mainly derived from the natural degradation of decabromodiphenyl ether by stepwise reductive debromination. Approximately 70% of Nona-BDE produced by Deca-BDE degradation could rapidly be degraded to form Octa-BDE. Approximately 85% of BDE-208 was derived from the degradation of BDE-209. During the degradation process from Octa-BDE to Penta-BDE, some Octa-BDE and Hexa-BDE homologues accumulated due to relatively slower degradation velocities, and the degradation rates of Penta-BDE to Tri-BDE were above 70%.

Synthesis of 4-Oxoisoxazoline N-Oxides via Pd-Catalyzed Cyclization of Propargylic Alcohols with tert-Butyl Nitrite.

A cyclization of propargylic alcohols with tert-butyl nitrite at room temperature in air was achieved using Pd(OAc)2 as catalyst. The first reported 4-oxoisoxazoline N-oxides could be directly accessed from a range of multisubstituted propargylic alcohols in moderate to excellent yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladium-catalyzed NO2 addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.

Eosin Y- and Copper-Catalyzed Dark Reaction To Construct Ene-γ-Lactams.

Eosin Y, a common organo-photocatalyst in visible-light photoredox processes, was found to show excellent catalytic activities for thermal redox reactions under a catalytic amount of Cu(OAc)2. With this catalytic system, vinyl azides and ketene silyl acetals combine to form formal [3 + 2] cycloadducts by α-ester radical addition without light irradiation. This method provides a mild and straightforward paradigm to prepare important synthons of five-membered ene-γ-lactams and bridge ring lactams. It is the first example of an eosin Y-catalyzed redox reaction in the dark.