Flavones and related compounds as inhibitors of protein tyrosine kinases

Aberrant tyrosine protein kinase activity has been implicated in the formation and maintenance of malignancy and so presents a potential target for cancer chemotherapy. Quercetin, a naturally occuring flavonoid, inhibits the tyrosine protein kinase encoded by the Rous sarcoma virus but also exhibits many other effects. Analogues of this compound were synthesised by the acylation of suitable 2-hydroxyacetophenones with appropriately substituted aromatic (or alicyclic) acid chlorides, followed by base catalysed rearrangement to the 1-(2-hydroxyphenyl)-3-phenylpropan-1,3-diones. Acid catalysed ring closure furnished flavones. The majority of the 1-(2-hydroxyphenyl)-3-phenylpropan-1,3-diones were shown by NMR to exist in the enol form. This was supported by the crystal structure of 1-(2-hydroxy-4-methoxyphenyl)-3-phenylpropan-1,3-dione. In contrast, 1.(4,6-dimethoxy-2-hydroxyphenyl)-3-phenylpropan-1,3-dione did not exhibit keto-enol tautomerism in the NMR spectrum and was shown in its crystal structure to assume a twisted conformation. Assessment of the biological activity of the analogues of quercetin was carried out using whole cells and the kinase domain of the tyrosine protein kinase encoded by the Abelson murine leukaemia virus, ptab150 kinase. Single cell suspension cultures and clonogenic potential of murine fibroblasts transformed by the Abelson Murine leukaemia virus (ANN-1 cells) did not indicate the existence of any structure activity relationship required for cytotoxicity or cytostasis. No selective toxicity was apparent when the `normal' parent cell line, (3T3), was used to assess the cytotoxic potential of quercetin. The ICS50 for these compounds were generally in the region of 1-100M. The potential for these compounds to inhibit ptab150 kinase was determined. A definite substitution requirement emerged from these experiments indicating a necessity for substituents in the A ring or in the 3-position of the flavone nucleus. Kinetic data showed these inhibitors to be competitive for ATP.

Electrochemical chloride extraction to halt corrosion of reinforcement

This thesis presents results of experiments designed to study the effect of applying electrochemical chloride extraction (ECE) to a range of different hardened cement pastes. Rectangular prism specimens of hydrated cement paste containing sodium chloride at different concentrations were subjected to electrolysis between the embedded steel cathodes and external anodes of activated titanium mesh. The cathodic current density used was in the range of 1 to 5 A/m2 with treatment periods of 4 to 12 weeks. After treatment, the specimens were cut into sections which were subjected to pore-solution expression and analysis in order to determine changes in the distribution of free and total ionic species. The effect of the ECE treatment on the physical and microstructural properties of the cements was studied by using microhardness and MIP techniques. XRD was employed to look at the possibility of ettringite redistribution as a result of the accumulation of soluble sulphate ions in the cement matrix near the cathode during ECE. Remigration of chloride which remains after the ECE treatment and distribution of other ions were studied by analysing specimens which had been stored for several months, after undergoing ECE treatment. The potentials of the steel cathodes were also monitored over the period to detect any changes in their corrosion state. The main findings of this research were as follows: 1, ECE, as applied in this investigation, was capable of removing both free and bound chloride. The removal process occurred relatively quickly and an equilibrium between free and bound chlorides in the specimens was maintained throughout. At the same time, alkali concentrations in the pore solution near the steel cathode increased. The soluble sulphate ionic concentration near the cathode also increased due to the local increase in the pH of the pore solution. 2, ECE caused some changes in physical and microstructural of the cement matrix. However these changes were minimal and in the case of microhardness, the results were highly scattered. Ettringite in the bulk material well away from the cathode was found not to increase significantly with the increase in charge passed.3, Remigration of chloride and other ionic species occurred slowly after cessation of ECE with a resultant gradual increase in the Cl-/OH- ratio around the steel.4, The removal of chloride from blended cements was slower than that from OPC.

Cathodic protection of reinforced concrete:anodic processes in cements and related electrolytes

The nature and kinetics of electrode reactions and processes occurring for four lightweight anode systems which have been utilised in reinforced concrete cathodic protection systems have been studied. The anodes investigated were flame sprayed zinc, conductive paint and two activated titanium meshes. The electrochemical properties of each material were investigated in rapidly stirred de-oxygenated electrolytes using anodic potentiodynamic polarisation. Conductive coating electrodes were formed on glass microscope slides, whilst mesh strands were immersed directly. Oxygen evolution occurred preferentially for both mesh anodes in saturated Ca (OH)2/CaC12 solutions but was severely inhibited in less alkaline solutions and significant current only passed in chloride solutions. The main reactions for conductive paint was based on oxygen evolution in all electrolytes, although chlorides increased the electrical activity. Self-corrosion of zinc was controlled by electrolyte composition and the experimental set-up, chlorides increasing the electrical activity. Impressed current cathodic protection was applied to 25 externally exposed concrete slabs over a period of 18 months to investigate anode degradation mechanisms at normal and high current densities. Specimen chloride content, curing and reinforcement depth were also variables. Several destructive and non-destructive methods for assessing the performance of anodes were evaluated including a site instrument for quantitative "instant-off- potential measurements. The impact of cathodic protection on the concrete substrate was determined for a number of specimens using appropriate methods. Anodic degradation rates were primarily influenced by current density, followed by cemendtious alkalinity, chloride levels and by current distribution. Degradation of cementitious overlays and conductive paint substrates proceeded by sequential neutralisation of cement phases, with some evidence of paint binder oxidation. Sprayed zinc progressively formed an insulating layer of hydroxide complexes, which underwent pitting_ attack in the presence of sufficient chlorides, whilst substrate degradation was minimal. Adhesion of all anode systems decreased with increasing current density. The influence of anode material on the ionic gradients which can develop during cathodic protection was investigated. A constant current was passed through saturated cement paste prisms containing calcium chloride to central cathodes via anodes applied or embedded at each end. Pore solution was obtained from successive cut paste slices for anion and cation analyses. Various experimental errors reduced the value of the results. Characteristic S-shaped profiles were not observed and chloride ion profiles were ambiguous. Mesh anode specimens were significantly more durable than the conductive coatings in the high humidity environment. Limited results suggested zinc ion migration to the cathode region. Electrical data from each investigation clearly indicated a decreasing order of anode efficiency by specific anode material.

Novel 5-HT7 ligands as antidepressants:automated synthesis of N-substituted-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfon amides

The 5-HT7 receptor is linked with various CNS disorders. Using an automated solution phase synthesis a combinatorial library of 384 N-substituted N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfonamides was prepared with 24 chemically diverse amines 1-24 and 16 sulfonyl chlorides A-P. The chemical library of alkylated sulfonamides was evaluated in a receptor binding assay with [3]H-5-CT as ligand. The key synthetic step was the alkylation of a sulfonamide with iodide E, which was prepared from butanediol in 4 synthetic steps. The target compounds 1A, 1B .....24A ... 24P were purified by solvent extraction on a Teacan liquid handling system. Sulfonamide J20, B23, D23, G23, G23, J23 , I24 and O24 displayed a binding affinity IC50 between 100 nM and 10 nM. The crystalline J20 (IC50=39 nM) and O24 (IC50=83 nM) were evaluated further in the despair swimming test and the tail suspension assay. A significant antidepressant activity was found in mice of a greater magnitude than imipramine and fluoxetine at low doses. © 2006 Bentham Science Publishers Ltd.

Geochemistry of the water column of southern lake Baikal during 1967-2005

At present, when the influence of human economic activity is progressively increasing, significant attention is devoted to the state of water ecosystems. All researchers engaged in these problems agree that the state of the water system (pollution and eutrophication) can only be estimated on the basis of long-term researches. Systemic monitoring (at least once per month) of ionic components (Ca2+, Mg2+, Na+, K+, bicarbonates, sulfates, and chlorides) in unfiltered water of Lake Baikal and its tributaries had been carried out under the supervision of Votintsev since 1947. Based on the analysis of systematic data on trophic components obtained during 1965-2005, we tried to estimate the present-day trophic status of the pelagic zone in the lake, define the trend of long-term changes of trophic components and understand the reasons of the distortion of cyclicity in the development of spring diatom algae, which create a favorable environment in any water basin. It should be noted that the station near Cape Polovinnyi is located 20 km away from the town of Baikal'sk. Wastewaters of the Baikal'sk pulp and paper mill is the main source of dioxins and furans in Baikal. Based on the significant difference between sulfate contents in wastewaters of the plant (>300 mg/l), tributaries of Baikal (7.5 mg/l), and waters in the southern part of the lake (3.9 mg/l), we defined the following periods: (i) period of natural seasonal patterns until 1967-1968 (prior to putting the Baikal'sk Mill into operation; (ii) period of weak anthropogenic pollution (1969-1985); and (iii) period of strong anthropogenic pollution since 1986.

Exceptional activity of gallium(III) chloride and chlorogallate(III) ionic liquids for Baeyer–Villiger oxidation

Baeyer–Villiger oxidation of cyclic ketones, using H2O2 as the oxidising agent, was systematically studied using a range of metal chlorides in different solvents, and in neat chlorogallate(III) ionic liquids. The extremely high activity of GaCl3 in promoting oxidation with H2O2, irrespective of solvent, was reported for the first time. The activity of all other metal chlorides was strongly solvent-dependent. In particular, AlCl3 was very active in a protic solvent (ethanol), and tin chlorides, SnCl4 and SnCl2, were active in aprotic solvents (toluene and dioxane). In order to eliminate the need for volatile organic solvent, a Lewis acidic chlorogallate(III) ionic liquid was used in the place of GaCl3, which afforded typically 89–94% yields of lactones in 1–120 min, at ambient conditions. Raman and 71Ga NMR spectroscopic studies suggest that the active species, in both GaCl3 and chlorogallate(III) ionic liquid systems, are chlorohydroxygallate(III) anions, [GaCl3OH]−, which are the products of partial hydrolysis of GaCl3 and chlorogallate(III) anions; therefore, the presence of water is crucial.

Avoiding Overfitting in Inverse Modeling of Chloride Migration in Concrete

Inverse analysis for reactive transport of chlorides through concrete in the presence of electric field is presented. The model is solved using MATLAB’s built-in solvers “pdepe.m” and “ode15s.m”. The results from the model are compared with experimental measurements from accelerated migration test and a function representing the lack of fit is formed. This function is optimised with respect to varying amount of key parameters defining the model. Levenberg-Marquardt trust-region optimisation approach is employed. The paper presents a method by which the degree of inter-dependency between parameters and sensitivity (significance) of each parameter towards model predictions can be studied on models with or without clearly defined governing equations. Eigen value analysis of the Hessian matrix was employed to investigate and avoid over-parametrisation in inverse analysis. We investigated simultaneous fitting of parameters for diffusivity, chloride binding as defined by Freundlich isotherm (thermodynamic) and binding rate (kinetic parameter). Fitting of more than 2 parameters, simultaneously, demonstrates a high degree of parameter inter-dependency. This finding is significant as mathematical models for representing chloride transport rely on several parameters for each mode of transport (i.e., diffusivity, binding, etc.), which combined may lead to unreliable simultaneous estimation of parameters.

Application of low temperature plasmas for restoration/conservation of archaeological objects

The low-temperature low-pressure hydrogen based plasmas were used to study the influence of processes and discharge conditions on corrosion removal. The capacitive coupled RF discharge in the continuous or pulsed regime was used at operating pressure of 100-200 Pa. Plasma treatment was monitored by optical emission spectroscopy. To be able to study influence of various process parameters, the model corroded samples with and without sandy incrustation were prepared. The SEM-EDX analyzes were carried out to verify corrosion removal efficiency. Experimental conditions were optimized for the selected most frequent materials of original metallic archaeological objects (iron, bronze, copper, and brass). Chlorides removal is based on hydrogen ion reactions while oxides are removed mainly by neutral species interactions. A special focus was kept for the samples temperature because it was necessary to avoid any metallographic changes in the material structure. The application of higher power pulsed regime with low duty cycle seems be the best treatment regime. The low pressure hydrogen plasma is not applicable for objects with a very broken structure or for nonmetallic objects due to the non-uniform heat stress. Due to this fact, the new developed plasmas generated in liquids were applied on selected original archaeological glass materials.

Contribuicao ao conhecimento dos efeitos da radiacao em cristais de KCl com impurezas de Sr

Tese (Doutoramento)

Elettrodeposizione di catalizzatori a base di Rh su schiume e fibre metalliche di FeCrAlloy per la produzione di syngas

The preparation of structured catalysts active in the catalytic partial oxidation of methane to syngas, was performed by electrosynthesis of hydroxides on FeCrAlloy foams and fibers. Rh/Mg/Al hydrotalcite-type compounds were prepared by co-precipitation of metallic cations on the support and successive calcination. Electrochemical reactions have been studied during the electrodeposition by linear sweep voltammetry. The experiments were performed at supports immersed in KNO3, KCl, Mg2+ and Al3+ aqueous solutions, starting by different precursors (nitrate and chlorides salts) and modifying the Mg/A ratio. Rh/Mg/Al hydrotalcite-type compounds were deposited on metal foams by applying a -1.2V vs SCE potential for 2000s with a nitrate solution of 0.06M total metal concentration. Firstly it was studied the effect of Mg on the coating propierties, modifying the Rh/Mg/Al atomic ratio (5/70/25, 5/50/45, 5/25/70 e 5/0/95). Then the effect of the amount of Rh was later investigated in the sample with the largest Mg content (Rh/Mg/Al = 5/70/25 and 2/70/28).The results showed that magnesium allowed obtaining the most homogeneous and well adherent coatings, wherein rhodium was well dispersed. The sample with the Rh/Mg /Al ratio equal to5/70/25 showed the best catalytic performances. Decreasing the Rh content, the properties of the coating were not modified, but the catalytic activity was lower, due to a not enough number of active sites to convert the methane. The work on metal fibers focused on the effect of precursor concentration, keeping constant composition, potential and synthesis time at the values of Rh/Mg/Al =5/70/25, -1.2V vs SCE and 1000s. However fibers geometry did not allow to obtain a high quality coating, even if results were quite promising.

Chemistry of potassium halides and their role in corrosion in biomass and waste firing

Compared to the use of traditional fossil fuels (coal, oil, natural gas), combustion of biomass and waste fuels has several environmental and economic advantages for heat and power generation. However, biomass and waste fuels might contain halogens (Cl, Br, F), alkali metals (Na, K) and heavy metals (Zn, Pb), which may cause harmful emissions and corrosion problems. Hightemperature corrosion occurs typically on furnace waterwalls and superheaters. The corrosion of the boiler tube materials limits the increase of thermal efficiency of steam boilers and leads to costly shutdowns and repairs. In recent years, some concerns have been raised about halogen (Cl, Br, and F)-related hightemperature corrosion in biomass- and waste-fired boilers. Chlorine-related high-temperature corrosion has been studied extensively. The presence of alkali chlorides in the deposits is believed to play a major role in the corrosion observed in biomass and waste fired boilers. However, there is much less information found in literature on the corrosion effect of bromine and fluorine. According to the literature, bromine is only assumed to play a role similar to chlorine; the role of fluorine is even less understood. In this work, a series of bubbling fluidized bed (BFB) bench-scale tests were carried out to characterize the formation and sulfation behaviors of KCl and KBr in BFB combustion conditions. Furthermore, a series of laboratory tests were carried out to investigate the hightemperature corrosion behaviors of three different superheater steels (10CrMo9-10, AISI 347 and Sanicro 28) exposed to potassium halides in ambient air and wet air (containing 30% H2O). The influence of H2O and O2 on the high-temperature corrosion of steels both with and without a salt (KCl) in three gas atmospheres (2% H2O-30% O2-N2, 2% H2O-2% O2-N2 and 30% H2O-2% O2-N2) was also studied. From the bench-scale BFB combustion tests, it was found that HBr has a clearly higher affinity for the available K forming KBr than HCl forming KCl. The tests also indicated that KCl has a higher tendency for sulfation than KBr. From the laboratory corrosion tests in ambient air (also called “dry air” in Paper III and Paper IV), it was found that at relatively low temperatures (≤ 550 °C) the corrosivity of KBr and KF are similar to KCl. At 600 °C, KF showed much stronger corrosivity than KBr and KCl, especially for 10CrMo9-10 and AISI 347. When exposed to KBr or KF, 10CrMo9-10 was durable at least up to 450 °C, while AISI 347 and Sanicro 28 were durable at least up to 550 °C. From the laboratory corrosion tests in wet air (30% H2O), no obvious effect of water vapor was detected at 450 °C. At 550 °C, the influence of water vapor became significant in some cases, but the trend was not consistent. At 550 °C, after exposure with KBr, 10CrMo9-10 suffered from extreme corrosion; after exposure with KF and KCl, the corrosion was less severe, but still high. At 550 °C, local deep pitting corrosion occurred on AISI 347 and Sanicro 28 after exposure with KF. Some formation of K2CrO4 was observed in the oxide layer. At 550 °C, AISI 347 and Sanicro 28 suffered from low corrosion (oxide layer thickness of < 10 μm) after exposure with KBr and KCl. No formation of K2CrO4 was observed. Internal oxidation occurred in the cases of AISI 347 with KBr and KCl. From the laboratory corrosion tests in three different gas atmospheres (2% H2O-30% O2-N2, 2% H2O-2% O2-N2 and 30% H2O-2% O2-N2), it was found that in tests with no salt, no corrosion occurred on AISI 347 and Sanicro 28 up to 600 °C in both the “O2-rich” (2% H2O-30% O2-N2) and “H2O-rich” (30% H2O-2% O2-N2) gas atmospheres; only 10CrMo9-10 showed increased corrosion with increasing temperature. For 10CrMo9-10 in the “O2-rich” atmosphere, the presence of KCl significantly increased the corrosion compared to the “no salt” cases. For 10CrMo9-10 in the “H2O-rich” atmosphere, the presence or absence of KCl did not show any big influence on corrosion. The formation of K2CrO4 was observed only in the case with the “O2-rich” atmosphere. Considering both the results from the BFB tests and the laboratory corrosion tests, if fuels containing Br were to be combusted, the corrosion damage of superheaters would be expected to be higher than if the fuels contain only Cl. Information generated from these studies can be used to help the boiler manufacturers in selecting materials for the most demanding combustion systems.