Diamino diamide copper complexes as anti-arthritic agents

Includes bibliographical references.This thesis describes the investigation of a series of diamino diamide copper(II) complexes with respect to their potential as anti-inflammatory agents in the treatment of rheumatoid arthritis. Several physico-chemical techniques were employed in the investigation including glass electrode potentiometry, UV/VIS spectroscopy, molecular mechanics calculations, speciation modelling as well as X-ray crystallography. Animal experiments were also carried out

Empirical Charge Scheme for Transition Metals and Lanthanoids: Development and Applications

Parameters for the fluctuating charge model are derived for In(III), La(III), Lu(III) and Bi(III), based on x-ray structural data and DFT single point calculations. A number of density partitioning schemes is tested

POLYCYCLIC POLYAMINES: SYNTHESIS AND CONFORMATIONAL ANALYSIS

The synthesis, conformational analysis, and reactivity of a homologous series of tricyclic orthoamides is discussed. The tricyclic orthoformamides, orthoacetamides, orthopropionamides, and orthobenzamides were synthesized by the uncatalyzed condensation of macrocyclic triamines with amide acetals. The conformations were studied spectrally (IR, (\u271)H NMR, (\u2713)C NMR, DNMR) and by the application of empirical force field calculations (MM2). In most (but not all) cases the minimized conformations as generated by MM2 were found to be in agreement with the experimentally determined conformations. The alkylation, acylation, and hydrolysis of these compounds is also discussed. Efforts towards the synthesis of the spherically shaped host molecule 1,5,9,13,-tetraazatricyclo{7.7.3.3(\u275,13)}-docosane are described. A classical acylation-reduction sequence was employed in this synthesis. Cyclizations were carried out under high dilution conditions. The design and construction of a new high dilution apparatus is described. High yields of monomeric cyclic intermediates were obtained. Monomeric cyclic intermediates were purified by preparative gel permeation chromatography (GPC). The modification of a Waters 200 analytical GPC unit are described as are the column packing procedures for preparative GPC columns

The solid state structures of metallo-beta-amino alcohol complexes

The ligands N,N’-bis(2-hydroxycyclohexyl)ethylenediamine (Cy2-en), and 2,2’-[(hydroxypropane-1,3-diyl)diimino]dicyclohexanol (Cy2-Otn) are synthesised and their solid state structures determined by X-ray diffraction experiments. Complexes are formed with the metal ions Pb2+, Cd2+, Ni2+, and Zn2+. The solid state structures of the lead(II) complex of Cy2-en and the cadmium(II) complex of Cy2-en are determined by X-ray diffraction experiments. Further complexations of the Pb2+ and Cd2+ ions are attempted with N,N’-bis(2-hydroxycyclohexyl)-1,3-propanediamine (Cy2-tn), and N,N’-bis(2-hydroxycyclohexyl) diethylenetriamine (Cy2-dien). The reactions are not successful. The ligand N,N’-bis(2-hydroxyethyl)ethylenediamine (BHEEN) is reacted with the metal ions Pb2+, Cd2+, Ni2+, and Zn2+, and the solid state structures of the cadmium(II) complex of BHEEN and the zinc(II) complex of BHEEN are determined by X-ray diffraction experiments. The solid state structures of both the ligands as well as the complexes indicate the presence of hydrogen-hydrogen bonds. The complexes contain more interactions than the uncoordinated ligands. Attempts are made to relate the interactions to the observed log K values for the complexes. Molecular mechanics calculations are performed to ascertain if a simple MM approach can suitably predict the conformations of the free ligands as well as the cadmium(II) complex of Cy2-en. The conformations of the free ligands are predicted well but the cadmium(II) complex of Cy2-en cannot be predicted without the addition of cadmium parameters to the GAFF force field

X-RAY INDUCED PHOTOREDUCTION OF REDOX ACTIVE METAL IONS

The use of synchrotron light sources has provided insights into structure, function, and mechanism of numerous proteins and enzymes. The fields of macromolecular crystallography and (MX) X-ray absorption spectroscopy (XAS) in particular have developed and grown with the use of synchrotrons, and cryoprotection has been an invaluable tool in making advances in these fields. Cryoprotectants have been employed to mitigate damage to biological samples caused by ice crystal formation during the flash cooling process. In addition, cryoprotectants are useful by allowing cryogenic temperatures to be utilized thereby reducing thermal vibrations in XAS experiments, and thermal stress on crystals used in MX experiments. X-ray induced photochemistry is an increasingly encountered problem for XAS experiments given the use of powerful synchrotron light sources with increased photon flux. As photon flux has increased, there has been a corresponding increase in X-ray induced photoxidation and photoreduction artifacts observed in XAS experiments. Increases in flux density have also been shown to have a negative impact on active site structure determination in MX experiments. Initial XAS studies of the prion protein (PrP) octarepeat region (OR) with Cu(II) revealed changes in the near edge region of the X-ray absorption spectra. After as little as one sweep of OR peptide bound to Cu(II), changes in the near edge region of the spectrum showed the loss of Cu(II) and an increase of Cu(I). Analysis revealed the complete loss of Cu(II) in situ and formation of Cu(I) bound to the PrP OR upon longer exposure to X-rays. To examine this phenomenon, samples of 2 mM CuCl2 with various cryoprotectants commonly used in XAS and protein crystal experiments were used in order to delineate the cause of the observed photoreduction. The preliminary result indicated that glycerol was the causative agent in exacerbating the X-ray induced photo-reduction. A series of experiments was then designed to examine the effects of glycerol concentration, copper concentration, and flux density on photoreduction rates. Results of these experiments show a linear relationship between the rate of photo-reduction and the X-ray flux density. Having observed photoreduction in aqueous copper samples, experiments were designed and carried out to exploit this phenomenon to produce chemically interesting mercury species. Given the previously observed relative stability of mercury at lower flux density values, the creation of Hg(0) species proved intriguing and relatively simple compared to other methodologies. Reports of peripheral sources of electrons contributing to photoreduction in experiments proved an intriguing addition to the photoreduction studies reported herein. Having studied photoreduction exacerbated by common cryoprotectants, studies were carried out with additional sources of electrons to observe any contributions made to photoreduction, including those present in common buffers used in both crystallographic and X-ray absorption spectroscopy experiments. Following examination of the increase in the rate of photoreduction with the presence of common cryoprotectants, experiments were designed and carried out to ameliorate the effects of photoreduction. Ketone groups have been long known to be excellent scavengers of free radicals and were examined to observe their presumptive protective effect on X-ray induced photoreduction