PolySNAP is a program used for analysis of high-throughput powder diffraction data. The program matches diffraction patterns using Pearson and Spearman correlation coefficients to measure the similarity of the profiles of each pattern with every other pattern, which creates a correlation matrix. This correlation matrix is then used to partition the patterns into groups using a variety of cluster analysis methods. The original version could not handle any data types other than powder X-ray Diffraction. The aim of this project was to expand the methods used in PolySNAP to allow it to analyse other data types, in particular Raman spectroscopy, differential scanning calorimetry and infrared spectroscopy data. This involves the preparation of suitable compounds which can be analysed using these techniques. The main compounds studied are sulfathiazole, carbamazepine and piroxicam. Some additional studies have been carried out on other datasets, including a test on an unseen dataset to test the efficacy of the methods. The optimal method for clustering any unknown dataset has also been determined.

No description available.

Circularly Polarised Luminescence (CPL) spectroscopy detects the differential emission of left and right circularly polarised light from luminescent chiral species, and so can be thought of as the emission analogue of circular dichroism spectroscopy. The circularly polarised emission of chiral europium complexes derived from the 12-ane-4 macrocycle cyclen, (examples of which are shown below) have been recorded using this technique. (Fig. 10701) These and similar complexes have shown an ability to bind to biologically important anions such as carbonate and phosphate in aqueous media and are able to report this event by a change in luminescence. These interactions have been investigated by monitoring the emitted circularly polarised light using the technique described and the binding of the substrate is clearly signalled. Typical CPL spectra of the europium complexes will be presented as will the binding study results and a detailed account of how the spectra is obtained.

The first part of this project focused on the effects of coadsorbates on the adsorption of organic molecules bonded to Cu(111). First, the influence of coadsorbed CO on the structure and bonding of thiophene was investigated using a combination of LEED, AES, TPD and synchrotron-based NIXSW and NEXAFS techniques. It was found that the coadsorption of CO does not induce an ordering of the disordered chemisorbed thiophene layer, in contrast to the behaviour of related benzene coadsorption systems where CO induces ordering of benzene disordered layers. Detailed analysis of our NIXSW and NEXAFS data showed that CO and thiophene both adopt stop adsorption sites within the coadsorbed overlayer, the same site adopted by both molecules in pure layers, and the orientation of the thiophene molecules within the coadsorbed layer is also similar to that adopted in the pure layer. The results of our NIXSW measurements, however, showed that CO molecules within the coadsorbed layer are tilted, which contrasts with a linear geometry observed in pure CO layers of a similar coverage. We propose that the lack of any significant coopertive effects between the CO and thiophene within the coadsorbed overlayers is due to the relatively weak adsorbate - substrate interactions. The second coadsorption study concerned the influence of sulfur precovered Cu(111) surfaces on the adsorption of thiophene, benzene, cyclohexene and cyclohexene molecules using TPD, AES, LEED, XPS, and UPS. The characterisation experiments established that all four molecules are reversibly adsorbed on all the surfaces studied, and more importantly our TPD and UPS data clearly showed that the co-adsorption of sulfur influences the bonding of each of the probe molecules in particular ways. At a pre-coverage of 0.12 ML of sulfur, the desorption of thiophene and benzene in our TPD experiments is shifted to higher temperatures, clearly showing that co-adsorbed sulfur at this precise coverage stabilises the adsorption of the aromatic molecules. With increasing S pre-coverage, the stabilising effects of similar on these two molecules diminish and by ca. 0.33 ML of sulfur destabilisation takes place. The stabilisation of cyclohexene is also effective but occurred at higher sulfur coverages (up to qS = 0.33 ML). We believe that steric blocking by sulfur adatoms is responsible for the destabilisation of thiophene, benzene and cyclohexene. For cyclohexene, however, stabilisation does not occur and the appearance of a new desorption peak indicates the formation of a less stable adsorption state at all sulfur coverages studied. We believe that the stabilisation of thiophene, benzene and cyclohexene on Cu(111) in presence of sulfur can be explained in terms of a simple electrostatic model. The formation of induced anti-parallel dipoles, which are caused by the charge transfer from the unsaturated molecules to the substrate and from the substrate to sulfur adatoms, provoke an increase of charge donation from the p-levels of the unsaturated molecules into unoccupied levels of the substrate. This model illustrates the enhancement of the bond strength of the p-bonded species to Cu(111) experimentally observed. A similar electrostatic model can also be used to describe the destabilisation of the cyclohexene molecules. The electrostatic field set up by sulfur results in the formation of induced parallel dipoles which reduce the charge transfer from the substrate to the saturated molecule and destabilise and saturated molecule. In the second part of this project, the surface reactivity of thiophene, benzene and benzonitrile with Si(100)-(2x1), Si(111)-(7x7) and Ge(100)-(2x1) was investigated using synchrotron-based valence band photoemission. To the best of our knowledge, the adsorption of thiophene and benzonitrile on the Ge(100)-(2x1) surface has not been reported in the literature. For the three molecules studied, our experimental results show that the relative reaction rates for the (2x1) semiconductor surfaces studied give Si(100) > Ge(100), with Si(100) being more reactive than the Ge(100) surface as a result of the higher degree of polarisation within the Si dimers than the Ge dimers. The detailed analysis of the collected valence band data reveals that the adsorption of thiophene, benzene and benzonitrile on all three semiconductor surfaces leads to the formation of 2,5-dihydrothiophene- 1,4-cyclohexadiene- and benzoimine-like moieties, respectively.

Synthetic routes from thebaine to l4β-acylaminodeoxydihydrocodeinones were explored. Each route was eventually frustrated by our inability to remove reductively either a 4-phenoxy or a 4-(1-phenyltetrazol- 5-yl)oxy group from a number of derivatives. Routes to the preparation of a thebaine derivative containing a piperidine nitrogen-carbon(14) bridge were investigated. In the N-northebaine series no bridged compounds were formed but in the thebaine series two quaternary ammonium chlorides with the desired bridge were prepared. Treatment of the cycloadduct 6β,14β-(N-chloroacetylepoxyimino)- 6,14-dihydro-N-t-butoxycarbonylnorthebaine with sodium ethoxide in ethanol afforded, unexpectedly, l4β-(2,2-diethoxyethanoylamino)-N-tbutoxycarbonylnorcodeinone. Similarly, the cycloadduct 6β,14β- (N-phenylacetylepoxyimino)-6,14-dihydrothebaine was found to react with high stereoselectivity with methoxide to give l4β-[(S)-2-methoxy-2- phenylethanoylamino]codeinone. Treatment of the hydroxamic acid l4β-(N-2-phenylethanoylhydroxyamino)codeinone with toluene-p-sulphonyl chloride in pyridine followed by methoxide gave a yellow product which had incorporated one molecule of pyridine. All the foregoing reactions are believed to proceed via aziridinone (α-lactam) intermediates. Further studies on model compounds supported the proposed mechanisms. An alternative, high yielding synthesis of the known a-lactam, l-t-butyl- 3-phenylaziridin-2-one, has been achieved by treating the appropriate hydroxamic acid with trifluoromethanesulphonic anhydride and triethylamine at 700 C. The reaction of the hydroxamic acid l4β-(N-chloroacetylhydroxyamino)- N-t-butoxycarbonylnorcodeinone ethylene acetal with ethoxide gave the l4β-aminonorcodeinone derivative. A similar treatment of the corresponding hydroxamic acid derived from thebaine and also of model compounds yielded ester products. These reactions are rationalised in terms of oxazetidinone intermediates.

The pigment Roseophilin is a novel antibiotic with a topologically unique skeleton incorporating an ansa-bridged 1-azafulvene core and an extended conjugated heterocyclic chromophore comprising furan and pyrrole moieties. Chapter one discusses the nature of this and related products and summarises the major contributions made towards their synthesis. Chapter two discusses the possible approaches to this complex natural product and outlines the proposed research. The proposed macrocyclisation step, the Nicholas reaction, is reviewed in the following chapter. The approach to the macrotricyclic core of Roseophilin is discussed in the ensuing chapters. Chapter four presents the initial strategy in which the [b]-fused pyrrole ring is constructed, by means of an aldol reaction onto a cyclopentanone frame. A second strategy in which the [b]-fused pyrrole ring is approached via a 1,4-dicarbonyl compound, involving the synthesis and use of molybdenum electrophiles is discussed in chapter five. A third and highly convergent strategy is presented in chapter six. This approach starts from pyrrole and makes use of the nucleophilicity of the heteroaromatic ring. The progress made in the approach to the macrotricyclic core is discussed. The building blocks for the isopropylsubstituted cyclopentanone ring are introduced via a Knoevenagel condensation 3-formylpyrrole and subsequent copper(I)-catalysed 1,4-addition. The reactive handle for the intramolecular macrocyclisation is introduced by a Sonogashira reaction at the 5-position of pyrrole. Finally the macrocyclisation studies, conclusions and perspectives are presented.

Our studies on the synthesis and biological evaluation of novel anticancer drugs consist of three research areas; namely, synthesis of Mitogen Activated Protein (MAP) kinase inhibitors, Checkpoint (Chk1) inhibitors and nordihydroguaiaretic acid (NDGA) analogues. The first research area involved synthesis of MAP kinase inhibitors. MAP kinases are a family of serine I and threonine II kinases which can act together to generate a process of phosphorylation events within the cell signalling pathway leading eventually to cell division. The compounds made in this project were specifically designed to target the stress related kinases, a MAP kinase pathway which controls the expression of genes involved in cell proliferation. The stress related kinases are known to have serine or threonine joined to a proline III residue. In an attempt to prepare selective inhibitors of stress related kinases, compounds of types IV and V were deigned in which a conformationally restricted serine analogue is joined to L-proline via an amide link in one of two possible ways. Examples of these two sets of compounds were synthesised and those that were tested by Professor David Gillespie at the Beatson Institute for Cancer Research, Glasgow were shown not to be inhibitors of these kinases. (Fig. 1144A) The second research area concentrated on the checkpoint signalling pathway. Components in the DNA damage checkpoint signalling pathway such as ChK1 could be potential targets for chemical intervention. Caffeine VI and pentoxifylline VII have been shown to sensitise p53-deficient tumour cells to killing by DNA damage. We envisaged that the xanthine derivatives, caffeine VI and pentoxifylline VII might also disrupt the G2 checkpoint by preventing activation of Chk1. To test his hypothesis, a range of xanthine derivatives shown below were prepared by alkylation of theophylline VIII or theobromine IX. (Fig. 1144B) The biological evaluation of these xanthine derivatives by Professor Gillespie revealed that three of these compounds, X, XI and XII, suppressed G2/M arrest very effectively. All three active compounds possess a long aliphatic chain that provides a large degree of flexibility to the structures. The long aliphatic chains could bind to a hydrophobic pocket in the enzyme’s active site that might confer selectivity on the compounds. (Fig. 1144C) The third area, synthesis of NDGA analogues, was the major part of the synthetic work. NDGA XIII is known to be a selective inhibitor of lipoxygenase and blocks small cell lung cancer growth in vitro and in vivo. In addition to its lipoxygenase activity, NDGA was demonstrated to inhibit c-kit, a tyrosine kinase that has been observed preferentially in SCLC. The main drawbacks to the use of NDGA in cancer treatment are its poor solubility and moderate potency. Therefore chemical modifications are required to provide better compounds for clinical use. Preliminary work in our group was performed by McDonald and Macleod. They synthesised a range of analogues of NDGA which were tested for their activity in vitro by Professor Michael Seckl at the Medical Oncology Department of Hammersmith Hospital, London. Improved potency over NDGA for new analogues with 4-6 atoms between the two aromatic rings was observed. Furthermore introduction of an amide linkage between the two aromatic residues resulted in NDGA analogues which are more active than NDGA. Based on these preliminary results, the structural modifications proposed for this project focused on three areas. The main programme of research was drug solubilisation of new analogues which have higher potency than NDGA for in vivo work. The second area of study sought to introduce position variations of the amide linkage between the two aromatic residues. The third area of work involved modification of the substituents on the two aromatic rings. (Fig. 1144D) A range of NDGA analogues was successfully synthesised and evaluated for anticancer activity in vitro. Compounds XIV and XV were confirmed as lead compounds which are ten times more active than NDGA. Compound XIV was successfully transformed into a water soluble form XVI which is now available for in vivo work. In addition NDGA was converted into a water soluble form which was more potent than NDGA in vitro. Moreover a NDGA analogue XVII with no free hydroxy groups was found to be as active as NDGA, which was an unexpected discovery. (Fig. 1144E)

No description available.

No description available.

The objective of the research that I have undertaken was to develop two quantitative techniques used in analytical electron microscopy, energy dispersive X-ray microanalysis (EDX) and electron energy loss spectroscopy (EELS) and to apply those techniques to a selected biological system. More specifically the aim was to develop a technique for quantifying, at high spatial resolution, trace concentrations of Al in mineralised bone. The Al was highly localised and therefore it was important to select the microanalytical technique with the required spatial resolution (m) compatible with the highest sensitivity. In practice, the choice was relatively simple because the signals from the trace concentrations could not be detected using EELS due to the combined effects of plural inelastic scattering in the sample, and a low signal to background ratio. The former problem resulted from the difficulty in preparing sufficiently thin samples, and the latter is an inherent problem of EEL spectroscopy. Therefore, EDX was chosen for the mineralised bone study. As is always the case, artefacts are introduced into the spectral data by the measurement system itself and it was necessary to first quantify these artefacts before attempting to process the EDX spectra. Standards of accurately known composition are often used to quantify the characteristic signals extracted from EDX spectra. Unfortunately, suitable standards were not available for the elements of interest. Therefore, a standardless quantitation procedure was used. Since the accuracy of the method was dependent upon the accuracy of the parameterised characteristic cross-sections, some time was spent determining the optimal parameterisation. Significant problems exist when attempting to extract the Al and Mg signals from the EDX mineralised bone spectra. Essentially these are due to the extensive overlap between the major P peak and the vanishingly small Al (and Mg) signals of interest. In addition it is difficult to model the bremsstrahlung background (for characteristic signal extraction) at the Al and Mg X-ray energies because of the combined effects of absorption in the detector and specimen, and incomplete charge collection in the detector. However, a technique was developed which greatly improves the accuracy of the characteristic signal extraction over existing methods. A new method of EEL spectral processing was developed in which the characteristic signals are separated from the background counts and quantified in a single process. This `single-stage' technique appears to have some advantages over the standard `extrapolation' method of spectral processing: e.g. when dealing with adjacent edge signals or small signals on relatively large backgrounds. A detailed investigation was made into all the problems associated with the application of EELS to the mineralised bone study of interest here; i.e. the difficulties of EEL mineralised bone specimen preparation and the very low Al signal/background ratio which is predicted, even if suitable mineralised bone samples could have been prepared. Finally, a brief investigation was made into the physiological implications of the mineralised bone atomic ratios obtained in the EDX study.