Structure-based discovery of novel α-aminoketone derivatives as dual p53-MDM2/MDMX inhibitors for the treatment of cancer.

The function of the p53 protein is impaired by the overexpression of its negative regulator murine double minute 2 protein (MDM2) and homologous protein MDMX. Disruption of the p53-MDM2/MDMX interaction to restore the transcriptional function of p53 is considered a promising strategy for cancer therapy. To design dual MDM2/MDMX inhibitors, the binding modes of MDM2 or MDMX with their inhibitors are elucidated. Several hot-spot residues of MDM2 or MDMX are identified by molecular dynamics simulations, alanine scanning and MM-GBSA calculations. Then, focusing on the interaction with hot-spot residues, two series of derivatives bearing 1,3-diketone and α-aminoketone scaffolds are designed and synthesized. Among these compounds, C16 is identified as the most potent compound with low micromolar binding affinities with MDM2 and MDMX. C16 also displays moderate antiproliferative activities against MDM2-overexpressing and MDMX-overexpressing cells, with IC50 values of 0.68 µM in HCT116 cells and 0.54 µM in SH-SY5Y cells. Furthermore, C16 inhibits cell migration and invasion, reactivates the function of p53, arrests the cell cycle and induces cellular apoptosis in HCT116 and SH-SY5Y cells. Collectively, C16 can be developed as a dual MDM2 and MDMX inhibitor for cancer therapy.

Mathematical modelling of sewage sludge incineration in a bubbling fluidised bed with special consideration for thermally-thick fuel particles.

Fluidised bed combustor (FBC) is one of the key technologies for sewage sludge incineration. In this paper, a mathematical model is developed for the simulation of a large-scale sewage sludge incineration plant. The model assumes the bed consisting of a fast-gas phase, an emulsion phase and a fuel particle phase with specific consideration for thermally-thick fuel particles. The model further improves over previous works by taking into account throughflow inside the bubbles as well as the floating and random movement of the fuel particles inside the bed. Validation against both previous lab-scale experiments and operational data of a large-scale industrial plant was made. Calculation results indicate that combustion split between the bed and the freeboard can range from 60/40 to 90/10 depending on the fuel particle distribution across the bed height under the specific conditions. The bed performance is heavily affected by the variation in sludge moisture level. The response time to variation in feeding rate is different for different parameters, from 6 min for outlet H2O, 10 min for O2, to 34 min for bed temperature.

Mathematical modelling of particle mixing effect on the combustion of municipal solid wastes in a packed-bed furnace.

Packed bed combustion is still the most common way to burn municipal solid wastes. In this paper, a dispersion model for particle mixing, mainly caused by the movement of the grate in a moving-burning bed, has been proposed and transport equations for the continuity, momentum, species, and energy conservation are described. Particle-mixing coefficients obtained from model tests range from 2.0x10(-6) to 3.0x10(-5)m2/s. A numerical solution is sought to simulate the combustion behaviour of a full-scale 12-tonne-per-h waste incineration furnace at different levels of bed mixing. It is found that an increase in mixing causes a slight delay in the bed ignition but greatly enhances the combustion processes during the main combustion period in the bed. A medium-level mixing produces a combustion profile that is positioned more at the central part of the combustion chamber, and any leftover combustible gases (mainly CO) enter directly into the most intensive turbulence area created by the opposing secondary-air jets and thus are consumed quickly. Generally, the specific arrangement of the impinging secondary-air jets dumps most of the non-uniformity in temperature and CO into the gas flow coming from the bed-top, while medium-level mixing results in the lowest CO emission at the furnace exit and the highest combustion efficiency in the bed.

Converting moving-grate incineration from combustion to gasification - numerical simulation of the burning characteristics.

Waste incineration is a politically sensitive issue in the UK. The major current technology is based on direct combustion of wastes in a moving-grate furnace. However, general public opinion prefers non-direct burning technologies. Waste gasification is one of those nearest technologies available. By reducing the primary air-flow rate through the grate of a packed-bed system, operation of the existing solid-waste incineration equipment can be easily converted from combustion mode to gasification mode without major modification of the hardware. The potential advantages of this are lower dust carry-over in the flue gases, lower bed temperature (and therefore lower NO(x) formation in the bed), simplified gas-treatment procedures and lower running cost, among other benefits. The major disadvantages are, however, reduced throughput of the wastes and possibly higher carbon in the ash at exit. In this study, numerical simulation of both combustion and gasification of municipal solid wastes in a full-scale moving grate furnace is carried out employing advanced mathematical models. Burning characteristics, including burning rate, gas composition, temperature and burning efficiency as a function of operating parameters are investigated. Detailed comparisons between the combustion mode and gasification mode are made. The study helps to explore new incineration technology and optimise furnace operating conditions.

Ignition and burning rates of segregated waste combustion in packed beds.

Recent developments in national recycling and re-use programmes for municipal waste have led to segregation of an increasing proportion of waste to enhance material recovery. Several of the segregated streams contain materials that can not viably be re-used or recycled but can be used for energy recovery. In this study, the combustion of cardboard and waste wood was investigated in a small-scale packed bed reactor in order to provide fundamental data for the design/operation of moving bed furnaces. Key parameters of combustion including the ignition and burning rates were evaluated for various air flowrates and compared to the modelling results. Two successive stages of combustion were identified for both samples: the propagation of ignition front into the bed and combustion of the fuel above the ignition front. The burning rate of cardboard reached a peak of about 300 kg/m(2)h at the air flowrate of 936 kg/m(2)h and decreased at higher air flowrates. For waste wood, both the ignition and burning rates increased in the tested range of the air flowrate up to 702 kg/m(2)h, of which the values were very close to those for the cardboard. The model prediction was in good agreement with the test results for waste wood. However, the burning rate for cardboard was under-predicted due to strongly irregular shapes of the fuel.