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An asymmetric organocatalytic cascade reaction has been reported for the rapid assembly of multifunctionalized α-carboline-spirooxindole hybrids, which suppressed proliferation in colorectal cancer cells.

SMYD3 is a histone methyltransferase involved in transcriptional regulation, and its overexpression in various forms of cancer justifies that blocking SMYD3 functions can serve as a novel therapeutic strategy in cancer treatment. Herein, a series of novel tetrahydrofuranyl spirooxindoles were designed and synthesized based on a structure-based drug design strategy. Subsequent biochemical analysis suggested that these novel SMYD3 inhibitors showed good anticancer activity against stomach adenocarcinoma both in vitro and in vivo. Among them, compound 7r exhibited potent inhibitory capacities against SMYD3 and BGC823 cells with IC

A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis. In vitro protein binding and cellular proliferation assays suggested that compound 5d was the most potent mouse double minute 2 homolog (MDM2) inhibitor. In addition, mechanistic studies indicated that compound 5d suppressed MDM2-mediated p53 degradation, induced apoptosis and promoted oxidative damage. Molecular docking studies have suggested that 5d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53. This work can provide a basis for the development of novel multifunctional MDM2 inhibitors. The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.

Inflammation can cause a series of inflammatory lung disease, which seriously endangers human health. Pulmonary fibrosis is a kind of inflammatory disease with end-stage lung pathological changes. It has complicated and unknown pathogenesis and is still lack of effective therapeutic drugs. LPS-induced inflammation is a common feature of many infectious inflammations such as pneumonia, bacteremia, glomerulonephritis, etc. Evodiamine, one of the main components of Evodia rutaecarpa, is an alkaloid with excellent antiinflammatory effects. In this study, we evaluated the protective capacities of evodiamine on LPS-induced inflammatory damages in vitro and in vivo. MTT method, flow cytometry, immunofluorescence, and other methods were used for in vitro study to determine the protective capacities of evodiamine. The results suggest that evodiamine can protect murine macrophages from the LPS-nigericin-induced damages by (a) inhibiting cellular apoptosis, (b) inhibiting inflammatory cytokines releasing, and (c) activating the apelin pathway. We also used the exogenous apelin-13 peptide co-cultured with LPS-nigericin in RAW264.7 cells and found that apelin-13 contributes to protecting the effects of evodiamine. In vivo, the ELISA method and immunohistochemistry were used to examine inflammatory cytokines, apelin, and histological changes. BALB/c mice were exposed to LPS and subsequent administration of evodiamine （p.o.）for some time, the results of the alveolar lavage fluid and the tissue slices showed that evodiamine treatment alleviated the pulmonary inflammation and fibrosis, stimulated apelin expression and inhibited the inflammatory cytokines. These results provide a basis for the protective effect and mechanism of evodiamine in LPS-induced inflammation and suggest that it might be potential therapeutics in human pulmonary infections.

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway, it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

Direct sulfide organocatalysis is an emerging topic in research on synthetic chemistry. Here, an unprecedented sulfide-catalyzed diastereoselective [4+1] annulation of (in situ generated) ortho-quinone methides and bromides is reported. Notably, the robustness of such sulfide organocatalysis was demonstrated by performing the catalytic reaction under oxidative conditions without significantly affecting the reaction outcome. Various dihydrobenzofurans with diverse substituents were obtained with high isolated yields of up to 98% and remarkable diastereoselectivity (>19:1 dr in general).

Here we report a secondary amine-catalyzed, highly enantioselective [3+3] cyclization reaction of α-alkylidene pyrazolinones and α,β-unsaturated aldehydes, which facilely delivers a variety of enantioenriched spiropyrazolones showing structural and stereochemical complexity. The reaction uses an iminium ion activation strategy to activate both the β- and ipso-positions of the enals as dielectrophilic sites. A broad range of substrates are compatible with this mild reaction system.

Laminated rubber bearings are constructed from alternating layers of rubber vulcanized to reinforcing steel shims, therefore, they can be treated as periodic structures. The transfer matrix method (TMM) is developed to analyze mechanical behaviors of the periodic bearings subjected to a compressive axial load and a lateral shear deformation. The periodic model can account for the effect of thicknesses, material properties and boundary conditions of each rubber and steel layer, on the details of mechanical behaviors between interlaminated layers. Haringx’s theory for the individual rubber layer and rigid body motion theory for the steel shim are utilized in the development of the model. Hence, the proposed approach overcomes Haringx’s theoretical drawback, which assumes the entire laminated rubber bearings as an equivalent continuous column, and is also a robust alternative to the stiffness matrix method through a complex assembly of a number of identical periodic elements. Comparisons with Haringx’s results show that TMM has good accuracy for analyzing laminated rubber bearings. The introduction of the pattern of periodic structure along with TMM provides a viable means for determining mechanical properties of laminated rubber bearings with different configurations by only changing the number of periodic elements and thicknesses of the layers.

The Ras-Related signaling pathway plays an important role in cell development and differentiation. A growing body of evidence collected in recent years has shown that the aberrant activation of Ras is associated with tumor-related processes. Several studies have indicated that indole and its derivatives can target regulatory factors and interfere with or even block the aberrant Ras-Related pathway to treat or improve malignant tumors. In this review, we summarize the roles of indole and its derivatives in the isoprenylcysteine carboxyl methyltransferase-participant Ras membrane localization signaling pathway and Ras-GTP/Raf/MAPK signaling pathway through their regulatory mechanisms. Moreover, we briefly discuss the current treatment strategies that target these pathways. Our review will help guide the further study of the application of Ras-Related signaling pathway inhibitors.

An efficient organocatalytic cyclization strategy was developed to synthesize pharmacologically interesting bicyclic imidazoline derivatives. Morita–Baylis–Hillman carbonates were applied as C3 electrophiles to react with N,C-dinucleophiles for the first time, yielding the desired products in good to excellent yields with outstanding diastereoselectivities. The optically pure bicyclic imidazolines were expeditiously prepared by utilizing the readily available chiral ketene aminals as building blocks. The products were found to inhibit MDM2–p53 binding and cell proliferation. The most potent compound 5c induced the accumulation of MDM2, p53 and p21 proteins in HCT116 cells and blocked interaction between MDM2 and p53.

A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids bearing a quaternary carbon center at the β-position of THN has been developed. The diastereodivergent direct catalytic Michael-aldol reaction between 3-ylideneoxindole and 2-methylbenzaldehyde was accomplished by using bifunctional tertiary amine. Simply changing the protecting group on the substrate in the organocatalytic cascade reaction led to inverted diastereoselectivity in good yields with a high ee value. To explain the diastereodivergence of the organocatalytic Michael-aldol cascade, we also proposed plausible transition-state models for [4 + 2] annulation based on the observed stereochemistry of the products.

Inhibitors of apoptosis proteins (IAPs) inhibit caspase activity, allowing various cancers to reduce programmed cell death (apoptosis) and resist drug treatment. The second mitochondrial-derived activator of caspases (SMAC) protein is an endogenous IAP antagonist, which can be considered as a potential anticancer therapy. Small-molecule SMAC mimetics based on the Ala-Val-Pro-Ile motif have been validated as potent IAP antagonists. In particular, most bivalent SMAC mimetics, which target both the baculovirus IAP repeat 2 (BIR2) and BIR3 domains in X-linked IAP (XIAP), antagonize IAPs better than the corresponding monovalent mimetics. Here we focus on strategies for designing bivalent small-molecule SMAC mimetics and progress in using them to antagonize IAPs. We also consider their clinical potential. Our discussion will hopefully help guide further study of these interesting mimetics.

The near-surface mounted (NSM) fibre-reinforced polymer (FRP) strengthening technique has become a viable strengthening method for reinforced concrete (RC) beams. Premature debonding failure of the NSM FRP strips is a common failure mode though that severely limits the effectiveness of the FRP intervention that results in reduced beam strength and deformability. The application of FRP U-jackets near the ends of the NSM strips offers a potential solution to the debonding problem. This paper presents the first systematic experimental investigation on the use of FRP U-jackets for delaying or preventing debonding failure in RC beams strengthened in flexure with tension face NSM FRP strips. A total of 11 large-scale RC beams were tested, with the investigated parameters being (i) arrangement of NSM carbon FRP (CFRP) strips, (ii) U-jacket material type, (iii) layout, width and inclination angle of FRP U-jackets. Failure modes, load-deflection and strain distribution responses of all tested beams were recorded. The test results bring clarity and understanding to the tested parameters and they also demonstrate the effectiveness of the U-jacket intervention.

The propagation and attenuation properties of waves in ordered and disordered periodic composite Timoshenko beams, which consider the effects of axial static load and structural damping, resting on elastic foundations are studied when the system is subjected to moving loads of constant amplitude with a constant velocity. The transfer matrix methodology is adopted to formulate the model in a reference coordinate system moving with the load. The localization factor is calculated to determine the wave velocity pass bands and stop bands. The interactions between the static axial load and moving load, structural damping and disorder on the bands are analyzed.

The fire resistance behaviour of tubular T-joints is experimentally and numerically investigated. Two specimens are tested to failure under a constant brace axial load at elevated temperatures. One specimen is reinforced with a collar plate at the brace/chord intersection and the other is not reinforced. Both specimens have identical geometric and material properties for comparison. The failure modes of the specimens without and with reinforcement are the local indent of the chord and the local indent of the chord with axial yielding of the brace, respectively. In the numerical study, a finite element (FE) package ABAQUS with a sequentially coupled thermal stress analysis is adopted to simulate the joint specimens. The FE and experimental results for the critical temperature, fire endurance time and failure mode are in good agreement. The FE method is subsequently used to conduct a parametric study. The failure modes and load ratio have a significant influence on the fire resistance of the joint. Finally, the critical temperatures obtained from the experiment and the numerical simulation are compared with the proposed equation derived from CIDECT and Eurocode 3. It is found that the proposed equation provides a reasonable prediction of the critical temperature of tubular joints reinforced with collar plates at load ratios ranging from 0.2 to 0.6.

Compared with the intensively studied C3 spirooxindoles, limited reliable approaches are reported for synthesizing structurally analogous C2-spiropseudoindoxyl derivatives. Here, we developed an efficient method for highly diastereoselective synthesis of cyclopropane-fused spiropseudoindoxyl derivatives (up to 88% yield and >20 : 1 dr in all cases) through [2 + 1] annulation of (Z)-2-ylideneoxindoles with sulfur ylides.

Vibration-based methods are promising for damage identification; however, their capabilities for damage identification under temperature variations are usually limited. In the paper, a vibr...

In this study, the real-time hybrid loading test system based on the velocity-based loading concept is developed. The test system utilizes the concepts of the real-time hybrid loading test method and the substructure technique to combine the loading process of rubber-bearing specimens and numerical modeling of bridge columns and girders. Newly developed components of the loading test system include: an axial loading device especially devised for the fast loading of rubber bearings, and a real-time test control algorithm using the velocity-based loading concept, implemented to a PC-DSP system framework for the actuator control signal processing. A series of real–time hybrid loading tests on natural rubber (NR), high-damping rubber (HDR), and super-high-damping rubber (HDR-s) bearings are conducted using the test system. The objective of this study is to pursue accurate prediction of the dynamic response and base isolation effects of rubber bearings under realistic earthquake conditions. Specifially, the base isolation effects of HDR-s bearing are discussed. Based on the test results, it is clarified that the HDR-s bearing is more effective than the HDR and NR bearings.

The electrochemical polymerization of methylene green has been carried out using cyclic voltammetry. The electrolytic solution consisted of 4° 10−3 mol/L methylene green, 0.1 mol/L NaNO3 and 1 × 10−2 mol/L sodium tetraborate with pH 11.0. The temperature for polymerization is controlled at 60°C. The scan potential is set between −0.2 and 1.2 V (vs. Ag/AgCl with saturated KCl solution). There are an anodic peak and a cathodic peak on the cyclic voltammogram of poly (methylene green) at pH≤3.8. Both peak potentials shift towards negative potentials with increasing pH value, and their peak currents decrease with increasing pH value. Poly (methylene green) has a good electrochemical activity and stability in aqueous solutions with pH≤3.8. The UV-Visible spectrum and FTIR spectrum of poly (methylene green) are different from those of methylene green.

A method for the shape finding of a specific type of self-anchored suspension bridge whose main cable is three-dimensionally curved is proposed in this study. The method, referred to as the coordinate iteration method (CIM), is developed from the force equilibrium features of the rational arch axis for suspension cables modeled by truss-cable elements. By establishing the linear iterative equations in terms of unknown coordinates and updating the relation matrices iteratively, a trial profile of the three-dimensional cable-only system easily and stably converges to the target system. The CIM is then extended to the shape finding of the total bridge system with the aid of a specific numerical model proposed in this study referred to as the indiscrimination coordinate rod model (ICRM). This model is used to simulate the core deformation effects of the total bridge. The detailed procedure undertaken to establish a finite-element model of the equilibrium system for the finished dead load state based on CIM and ICRM is also presented. The precision and efficiency of the method are demonstrated through actual numerical examples.

Piezoelectric lead zirconate titanate (PZT) transducer in the electromechanical impedance (EMI) technique has emerged as a potential sensing tool for structural health monitoring. In the EMI technique, PZT acts as both sensor and actuator simultaneously due to its direct and inverse piezoelectric effects. The EMI method using PZT transducers provide a new way for in-situ nondestructive testing of concrete strength development since the conventional nondestructive detection techniques have many limitations. This paper presents an experimental study on monitoring the concrete cubes' compressive strength based on embedded PZT impedance transducers. By monitoring the PZT admittance (inversion of impedance) signals in different concrete ages the compressive strength development of concrete is predicted qualitatively. In addition, combining with the index of the resonant frequency, the correlation between concrete strength and the resonant frequency of the PZT admittance is founded. In the study, the feasibility of the EMI method based on embedded PZT transducers for monitoring the concrete strength development in early ages is verified, and it is found that the resonance frequency of the PZT admittance has a good reflection to the concrete age and the strength development of concrete.

Piezoelectric ceramics (PZT) is one of smart materials, which holds direct and converse piezoelectric effects and can use as impedance transducer for structural health monitoring. However, the PZT transducers must be waterproofed when they are embedded into the concrete structure to monitor the inner stress field since the PZT is a type of moisture absorption material. In this paper, three different waterproof materials, asphalt lacquer, silica gel, and general asphalt are used to overlay the PZT transducers respectively. Subsequently, the real admittances of the inundated PZT transducers are test by the impedance analyzer PV70A. The test results show that the admittance curves of PZT transducer overlaid by asphalt lacquer hardly vary before and after the PZT transducers are inundated into water, which suggests that asphalt lacquer is a fine waterproof material for PZT transducer.

The representative of carotenoids, beta-carotene, can scavenge reactive oxygen radicals like singlet molecular oxygen, nitrogen dioxide radical and peroxyl radical due to the effective antioxidative properties. In medicine, beta-carotene is used to alleviate the disease erythropoietic protoporphyria (EPP), by intercepting the triplet state of protoporphyrin (a porphyrin lacking a central metalion, a precursor to haem) therefore preventing the formation of singlet oxygen. Epidemiological evidence has suggested that dietary beta-carotene may inhibit certain types of cancer. Much of work has been carried out in benzene, toluene, or chloroform as most caroienoids are sufficiently soluble in these nonpolarity solvents. In the present paper, the generation and properties of triplet beta-carotene in acetonitrile solution were investigated with 355 nm laser flash photolysis. 2-acetonaphthone was used as an excitation energy donor to sensitize the production of the triplet state of beta-arotene. Excitation of the solution containing 2-acetonaphthone and beta-carotene upon 355 nm laser flash produced the triplet of 2-acetonaphthone (420 nm) firstly. Subsequently, the excitation energy of triplet 2-acetonaphthone was transferred to beta-carotene generating triplet beta-arotene. Characteristic absorption spectra of triplet beta-arotene (510 nm) were recorded. By means of transfer of excitation energy, the molar absorption coefficients of triplet beta-arotene were determined to be 23 000 dm3 mol(-1) x cm(-1) at 510 nm. The triplet lifetime for beta-carotene in acetonitrile solution was observed to be 15.6 micros. The rate constant for the reaction of triplet energy transfer from triplet 2-acetonaphthone to beta-carotene was calculated to be 1.5 x 10(10) dm3 x mol(-1) x s(-1). Obviously, the triplet beta-carotene has very low excitation energy. Taking the advantage of the photochemical properties of triplet beta-carotene, beta-Carotene has been widely used as energy acceptor to determine the excited state characteristic of other substance. This work extends the understanding of photochemical properties of beta-carotene.