In this work a number of yeast species were assessed for their potential in testing putative toxic and genotoxic compounds. Carbon tetrachloride (CCÍ4) was used as a model compound. Exposure of cells of Schizosaccharomyces pombe and Saccharomyces cerevisiae to carbon tetrachloride showed that the compound was toxic to the cells in a dose-dependent manner. Sch. pombe was more sensitive to the effects of carbon tetrachloride than S. -cerevisiae. Administration of the anti-oxidant a-tocopherot (vitamin E) to ceils of Sch, pombe treated with a toxic dose of carbon tetrachloride appeared to increase cell survival. Thèse data are consistent with work carried out on mammalian cells, and indicate that the toxic effects of carbon tetrachloride are brought about via the generation of free-radical species. Investigation of the genotoxicity of carbon tetrachloride in Sch. pombe and S. cerevisiae revealed that the compound induced mutations to chloramphenicol resistance at concentrations which were toxic to the cells. Carbon tetrachloride also induced forward mutations in Sch. pombe ade6. Genetic analysis of chloramphenicol resistant mutants indicated non-Mendelian inheritance. The drug-metabolising enzyme cytochrome P450 is thought to metabolise carbon tetrachloride to toxic species. The ability of carbon tetrachloride to act as a substrate for the haemoprotein was indicated by the type 1 binding spectrum produced in Sch. pombe. a-Tocopherol was found to increase levels of cytochrome P450. The production of cytochrome P450 was investigated in the three yeast species Sch. pombe, S. cerevisiae and Candida parapsitosis. The enzyme was optimally produced under conditions of glucose repression during the late logarithmic phase of growth. Levels of the enzyme were consistently found to be greater in respiratory deficient (petite) mutants of the yeast S. cerevisiae than in wild type strains. The enzyme was isolated from microsomal preparations of C. parapsilosis. SDS-PAGE analysis revealed a major band in the solubilised fraction possessing a molecular mass of approximately 48 kDa which was tentatively identified as cytochrome P450.

Thallium-205 chemical shifts have been determined for organothallium(III) derivatives RTlx2 and R2TlX (R = alkyl alicyclic, alkenyl,aryl ; X = anion). ... Twenty four new organothallium(III) derivatives have been synthesised and a number of existing syntheses modified.

The protonation end complexetion behaviour of the a-aminomethylenephosphonic acids diethylaminomethylenephonosphonic acid (DEAMPH2), N-ethyliminobis(methylenephosphonic acid) (NEIBMPH4), (+-)-trans-l,2-diaminecyclohexane tetrakis(methylenephosphonic acid) (CDTMPN8) and 5,8-dioxadodecane-1,12-diaminetetrakis(methylenephosphonic acid) (DDDTMPH8) were studied by potentiometry and near spectroscopy.

The synthesis and structure of 1,2-quinone mono-oximes have been reviewed. The reaction of 3-hydroxyphenol, 3-hydroxy-2-aethylphenol, 3-hydroxy-5-methylphenol and N-acetyl-3-aminophenol with amyl nitrite/M(OEt) (M - Na or K) has been systematically examined. It has been found that the complex formed depends on the reaction temperature and phenol/M(OEt) ratio. Infra-red spectroscopic studies have shown that in the solid state 5-hydroxy-l,2-benzoquinone 2-oxime (hqoH,), 5-hydroxy-3-methyl-l,2-benzoquinone 2-oxime (3-MehqoH2), 5-hydroxy-6-methyl-l,2-benzoquinone 2-oxime (e-MehqoH,) and H-acetyl-5-amino- 1,2-benzoquinone 2-oxime (N-AcqoH) and their sodium and potassium complexes exist in the oximic form rather than the nitroso form. Nuclear magnetic resonance studies have also shown that in d,-DHSO solution hqoH,, 3-MehqoH, and 6-MehqoH} and their sodium complexes exist in one form only which is oximic in character. However, in DjO the results for the sodium complexes of hqoH, and e-MeqoH, indicate the presence of at least two species. In the case of the sodium 5-hydroxy-6-methyl-l,2-benzoquinone 2-oximate these species are oximic in character. An X-ray crystallographic study of e-HehqoH, has shown that in the solid state this compound exists in the 1,4- rather than the 1,2-quinone 2-oxlmic form. The synthesis of iron(II) complexes of hqoH,, 3-MehqoH] and 6-HehqoH] using the direct and the nitrosation methods was examined. The direct method gave rise to the complexes Fe(hqoH), OHjO, Fe(3-HehqoH), and Fe(6-MehqoH)2 '2H20 whereas the nitrosation method gave rise to ill-defined solids. Na[Fe(N-Acqo), ]-4H20 was obtained by nitrosation of N-acetyl-3-aminopnenol in the presence of Iron(II) ammonium sulphate. Hossbauer and magnetic studies indicate that Na[Fe(N-Acqo)j]-4H20 is a low spin iron(II) complex whereas the bischelates have properties indicative of the S - 1 spin state. In-vlvo assesment of the iron chelating ability of hqoHj, 3-MehqoH2, 6-MehqoH2, N-AcqoH , N,N-dimethyl-5- amino-1,2-benzoquinone 2-oxime and violuric acid was carried out using a normal rat model. The chelators hqoH, and 6-HehqoH2were found to be effective in removing iron when administered intra-muscularly but they also caused the excretion of magnesium. Their activity was lower than that of desferrioxamine and neither was effective when administered orally.

A review is presented on the historical background to the development of primary cells, their performance characteristics and their fundamental electrochemistry.

This Thesis describes X-ray crystallographic investigations on twelve compounds. The first three are the products of the acid condensation of ortho-aminobenzaldehyde, OAB, the so-called TAAB salts, based on the tetra-anhydro tetramer of OAB. Although known since 1926, their structures have remained controversial. Of the three salts, TAABH2(X)2, investigated, that of X = picrate was found to be ordered, whilst those of X = HSO4 and BF4 were disordered. The structure of the TAABH2 cation is saddle-shaped and based on a fused heptacyclic framework. In all the three salts the anion appears to be doubly hydrogen bonded to the cation, through hydrogen donors NH and CH. The results enable a controversy in the literature regarding the structures of these compounds to be resolved. The self-condensation products of anthranilic acid, AA, also somewhat controversial in nature, have been investigated. The formation of a trimeric, and minor yields of a tetrameric derivative, is confirmed. The crystal structures of the tetramer and of two solvates of the trimer (CHCI3 and CH3CN.H2O) were determined. These two compounds, also, have a fused heptacyclic double saddle-shape overall structure. Their structures are compared with those of the TAAB salts. Related types of hydrogen bonding are surveyed, and the results found in this Thesis are put in a wider context. The structure of the copper complex Cu(TAABH2 ) of reduced TAAB derivative TAABH4, a 16-membered tetra-azamacrocycle has been investigated. It, too, has an overall saddle-shape, but this is considerably flatter than those of the TAAB salts and AA derivatives. Two metal complexes (CuII and Felll) of a 14-membered tribenzotetra-azamacrocycle were investigated. In the case of the iron compound. X-ray crystallography showed that an unexpected, novel oxygenation reaction of the ethylene bridge had taken place to give an a,B-diketo group. The purpose-made copper diketo-analogue was examined for comparative purposes. This derivative, in contrast to that based on TAABH4 , has an almost square planar co-ordination around the copper atom. A compound, thought to have been the free parent ligand of these metal complexes, was also investigated. The data set was poor, but it could be shown that the compound was acyclic, contained an extra ortho-phenylene diamine residue, and was probably hydrogen bonded. The crystal structures of two metal complexes based on Cull and Felll of two dibrominated Schiff bases were investigated. The dibrominated copper salen derivative is monomeric, in contrast to the unbrominated compound, which is dimeric. The Felll derivative, like the earlier-mentioned oxidised tetra-azamacrocyclic iron derivative, has a dimeric structure, with the iron atoms linked by a p(?)-oxo-bridge. The structures of the three copper and two iron derivatives are discussed and compared. Three themes emerge from the twelve structures described in this Thesis: (i) the structural importance of hydrogen bonding, (ii) the inadequacy of a single valence bond formulation to explain the observed X-ray crystallographic results, and the need to invoke resonance forms, mainly ortho-quinonoid, and (iii) the versatile role of nitrogen in organic and metal organic heterocyclic structures.

This Thesis describes the measurement and interpretation of diffuse optical scattering from concentrated colloidal dispersions. Novel measurement techniques using optical fibres are investigated. These are applied to monodisperse spherical latexes where the results are compared with theories of radiative transport, and also to plate-like Kaolinite particles where non-random particle orientation by shear flow is studied at small and large Reynolds number. For the spherical latex dispersions various fibre configurations are investigated, the results being compared with multiple scattering predictions of the inverse scattering length S. All configurations give values of S which show the theoretical particle size dependence, but the single fibre bundle gives S in good absolute agreement with that calculated from an accepted approximate solution to the radiative transport equation. Comparisons of S between the single fibre bundle and the conventional integrating sphere method show good agreement, but only after making large specular reflectance corrections in the latter case. Measurements made on latex volume fractions (v) up to 0.4 showed a maximum in S at about v = 0.2, Interpreted as non-random destructive interference between ordered particles. For the kaolilnite dispersions S is measured as a function of shear rate, volume fraction, particle size, pH and deflocculant concentration. Using the anomalous diffraction and Rayleigh-Gans light scattering approximations, calculations are given which support a mods of particle orientation expected below the critical Reynolds number from the particle hydrodynamics over a wide range of rotational Peclet number. The results for concentric cylinder flow above the critical Reynolds number are explicable in terms of Taylor vortices. The shear-induced changes in S in laminar flow are shown to be a useful practical measure of the state of flocculation of the dispersion.

A study of preparation methods for alpha-aminoalkanephosphonic, alpha-aminoalkanephosphonous and alpha-aminoalkanephosphinic acids has been made, based on the combined use of an aldehyde, an amino com pound, and a phosphorus reagent. Reported yields are frequently poor and the mechanisms of the reactions are unclear. The synthesis of alpha-aminoalkanephosphonic acids has been systematically examined. Propanal was used as a model carbonyl compound in reaction with various combinations of the following: 1) (PhO)3P, (PhO)2PH, (MeO)3P, (MeO)2PHO, (Et0)2PH0, PCI3, H3PO3. 2) H2NC02Et, H2NC02CH2Ph, H2NCH2Ph, H2NCHPh2, H2NCONH2 , H2NC0NHPh. NH3. The yields of various routes developed have ranged from 65% to 12%. The products have been fully characterised by melting point, elemental analysis, and nmr (1H,13C,31P) spectroscopy. Radiolabelled alpha-amino4 -[14C ]-propanophosphonic acid was prepared for toxicology studies. An interesting feature of this compound has been the formation of chemically identical crystalline products whose melting points differ by 10°C after repeated recrystallisation. The crystal structure of alpha-amino4-[14C]-propanephosphonic acid was determined in order to examine the possibility of different crystalline forms. 31P nmr spectroscopy studies of "one-pot" syntheses of the alpha-aminopropanephosphonic acid have shown that low yields may be due to the formation of several phosphorus-containing by-products and not merely from the problems of isolation. A range of a-aminoalkanephosphonous acids and their derivatives has been prepared and characterised by nmr (1H,13C, 31P) spectroscopy. These acids were also examined by FAB mass spectrometry and were found to give strong [M+H]+ ions. New derivatives of alpha-aminopropanephosphonic acid were prepared and characterised. Results of screening tests have been presented.

1-Aminoalkanephosphonic acids and their derivatives, have long been claimed to be compounds with a wide variety of application. Numerous examples exist where they have been described as: complex-forming agents with sequestrating properties, extractants, wetting agents, pharmaceutical preparations, ion exchangers, herbicides, compounds with plant growth regulatory activity; inhibitors of aminopeptidases; as structural units in peptide analogues, functioning as antibacterial agents, which inhibit bacterial cell wall biosynthesis; as structural units in peptidic phosphonylating agents that irreversibly inhibit a wide variety of serine proteases; as structural units in butyloxycarbonyl protected phosphonate esters that complex with alpha-lytic proteases; and as structural units in peptidyl phosphonate diphenyl 9 10 esters which powerfully inhibit the enzyme thrombin. ...

The involvement of chemically-reactive oxygen radical species (RORS) in the pathogenesis of inflammatory joint diseases has been well documented. Much of the toxicity produced by increased superoxide ion (O2.-) and hydrogen peroxide (H2O2) generation has been attributed to the production of the highly reactive hydroxyl radical (.OH) which is mediated by low-molecular-mass iron chelates such as iron-citrate complexes. The .OH radical is extremely reactive and proving its formation in vivo is very difficult. Hence, assays for the assessment of .OH radical activity in the inflamed rheumatoid joint have involved identification and/or quantification of ‘unnatural’ chemical species produced by the attack of OH radical on a range of endogenous or, alternatively, therapeutically-administered exogenous 'target' molecules. This study involves: (1) An investigation of the precise chemical nature of intermediates in and so called 'endproducts' of the process of lipid peroxidation. Second-derivative (2D) electronic absorption spectrophotometry has been applied to the analysis of isomeric conjugated hydroperoxydienes, hydroxydienes and ketodienes and also to thiobarbituric acidreactive material in synovial fluid (SF) obtained from patients with inflammatory joint diseases. (2) A method for determining the extent of RORS-dependent peroxidation of polyunsaturated fatty acids (PUFAs) has been further developed for application to biological samples. This technique involves the conversion of conjugated hydroperoxydienes and compounds derived therefrom, i.e. oxodiene and hydroxydienes, to strongly chromophoric conjugated triene and tetraene species. The chromophore(s) produced are measured by their absorbance in the ultra-violet or near ultra-violet regions of spectra using 2D spectrophotometry. (3) An evaluation of the chemical nature of non-transferrin-bound iron in inflammatory synovial fluid is investigated by high-resolution, high-field proton (1H) nuclear magnetic resonance (NMR) spectroscopy, combined with the use of powerful iron(III) chelators (desferrioxamine and nitrilotriacetate), and the iron(lII)-binding protein apotransferrin in order to 'speciate' catalytic, low-molecular-mass iron complexes present in inflammatory SF samples. (4) The application of high field proton NMR spectroscopy to evaluate the abilities of the antioxidant thiol drug N-acetylcysteine and exogenous cysteine to protect metabolites present in intact inflammatory SF samples against oxidative damage arising from reactive oxygen radical species generated via gamma-radiolysis (5.00 kGy) in the presence of atmospheric oxygen.