Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.
To further improve the electrochemical performance of electrode materials for supercapacitors, we have achieved a significant increase of the micropore volume of a MnO2 hybrid film on IrO2 nano-wedges grown on a pre-treated Ti plate by the co-doping of vanadium and iron (V+Fe). X-ray diffraction and microstructural analyses demonstrate that the V+Fe co-doped MnO2 hybrid films consist of the lamellar structure that is composed of γ-MnO2 nanocrystallites jointed by disordered interface. Nitrogen sorption analysis confirms that the pore characteristics of the MnO2 film change from mesopore-dominant to micropore-dominant after the co-doping, accompanied by increases in the pore volume and specific surface area. The specific capacitance of the V+Fe co-doped MnO2 hybrid film electrode declines from 426 F g−1 to 314 F g−1 with a relatively limited loss of 26% when the galvanostatic (GV) charging-discharging rate is increased from 0.2 to 5 A g−1. In particular, the doped MnO2 film electrode has a loss of only 6% in the specific capacitance after 9000 cycles at a charge-discharge current density of 10 A g−1.
38CrMoAl nitriding layer had been prepared by plasma electrolytic nitriding under different concentration of ammonia water. The layer structure, surface and phase composition had been analyzed by OM 、 SEM 、 XRD, respectively. Deeper analysis about element distribution in layer had been implemented by GDOES. The layer corrosion resistance had been measured by Parstat2273 Electrochemical workstation. microhardness and the wear properties of specimens were also evaluated. The experiment results show that: the nitriding layer consist mainly of Fe 2 N and Fe 3 N, the layer thickness is 85±5 to 165±15 μm and the cross-section microhardness of the layer is 650- 1023HV after treated 10 min at 220 V. When the concentration of ammonia water drops to 40%, FeO is observed in outer-layer. The intensity of the maximum diffraction peak changed with the varying of nitrogen concentration. With the increasing of ammonia water concentration, the thickness of uniform and compact the white layers increases, the diffusion layers consist of needle nitrides and small carbides first increases then decreases, the distance for the biggest microhardness position to the surface increases obviously. After treated at 60% ammonia water, the layer thickness would get 165 μm, the diffusion layer reach 114 μm, microhardness of the layer reach 1023HV while the substrate hardness remain 310HV. Compared with the treated sample, the untreated wearing weight increase 4.5 times. The corrosion potential had been improved greatly from -523.4 mV to -464.1 mV. The white layer reaches 52 μm while the ammonia water reaches 70. However the diffusion layer is thinner, so the layer thickness decrease gradually.
Abstract The hydrolytic kinetics of acetylsalicylic acid in different microemulsion systems have been studied. The results show that the hydrolytic rate is affected by the microemulsion structure and the type of surfactant. The break points of the hydrolytic rate are correspond to the break points in diffusion coefficient and in conductivity that we assign to the W/O, O/W, and bicontinuous structural transitions in the microemulsion single-phase regions. Keywords: MicroemulsionAcetylsalicylic acidHydrolysis ACKNOWLEDGMENT This project (Nos. 29733110, 20073038) was supported by the Natural Scientific Research Foundation of China.
We demonstrate here that RNA levels of 25-hydroxy-vitamin D3-24-hydroxylase (24-(OH)ase), a key catabolic enzyme for 1,25-dihydroxyvitamin D3, are increased by a highly selective retinoid X receptor (RXR) ligand, LG100268, in mice within hours. Correspondingly, upon LG100268 treatment, kidney 24-(OH)ase enzymatic activity increases 5-10-fold. The endogenous retinoid hormones, all-trans-retinoic acid and 9-cis-retinoic acid, and the synthetic retinoic acid receptor-selective compound, TTNPB, also stimulate 24-(OH)ase. Additionally, we show that LG100268 stimulates transcription of a luciferase reporter plasmid driven by 24-(OH)ase promoter sequences in the presence of RXR in CV-1 cell cotransactivation assays. This first demonstration of a gene that is regulated in the intact animal through an RXR-mediated pathway confirms earlier hypotheses that RXR is a bona fide hormone receptor. Regulation of a key gene in the vitamin D signaling pathway by a retinoid transducer may provide a molecular basis for some of the documented biological effects of vitamin A on bone and vitamin D metabolism.
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