Complexation of trivalent lanthanides by three diphosphonate ligands in the blood plasma

It has been shown that ¹⁵³Sm complexed with the bone seeking ligand ethylene-diaminetetramethylene phosphonate (EDTMP) is effective in pain palliation therapy of bone cancer. Blood plasma models for this ligand with Sm(III) and Ho(III) have been successfully constructed explaining the differences between ¹⁵³SmEDTMP and ¹⁶⁶HoEDTMP. The latter isotope is preferred because of its more energetic β particle, thought to improve the therapeutic effect of the radiopharmaceutical. However, ¹⁶⁶HoEDTMP is not an effective pain palliation agent and consequently the search for a more effective bone cancer therapeutic radiopharmaceutical involving ¹⁶⁶Ho continues. A ligand is being sought which complexes Ho(III) with a formation constant high enough to survive competition from blood plasma ligands but not so high to prevent ¹⁶⁶Ho from being accessible to metastases. EDTMP is unsuitable as such a ligand because of its inability to compete with citrate for complexation of Ho(III). For this study three diphosphonate ligands applied in radiation imaging of bone or nonradiative treatment of osteoporosis were chosen. They are APD (1-hydroxy-3-aminopropylidene- diphosphonic acid), MDP (methylenediphosphonic acid) and HEDP (1- hydroxy-ethylene-diphosphonic acid). Formation constants for the complexation of Ca(II), Mg(II), Zn(II), Sm(III) and Ho(III) with all of these ligands were measured using potentiometry and polarography. The latter was used to complement potentiometry in systems where precipitates formed. The complexation of Cd(II) by HEDP was used to compare the two techniques and to show that the values found by either technique are comparable. NMR studies were attempted on some complexes in solution to investigate the role the of the hydroxy-group (APD and HEDP) in complexation. The program ECCLES was used together with the formation constants measured in this study to predict the speciation of Ho(III) and Sm(III) with these three ligands in blood plasma. The results gathered for Ho(III) and APD were used as an indication and in an application to an ethical committee before animal testing. A baboon test was carried out using ¹⁶⁶HoAPD, the most promising system. The resulting bone-uptake and side-effects found in the animal study confirmed the predictions made by ECCLES. It proved that ¹⁶⁶HoAPD would be ineffective as a therapeutic agent due to high liver uptake. Valuable information on how a future radiopharmaceutical should be designed was obtained in this study

Homogenous transition metal

Faculty of Science School of Chemistry 0100505x [email protected] application of homogenous transition metal catalysis to the arylation of enolates to develop new synthetic procedures which are more environmentally benign, atomefficient and economically viable than current methods was the motivation behind the current work. The specific choice of molecules with an aromatic group in the a- position of a ketone, carboxylic acid, amide or other electron-withdrawing group arose from the fact that many natural products, pharmaceutical actives and synthetic intermediates contain such a substructure while the syntheses of these substructures are often cumbersome. The application of homogenous catalysis to various types of enolates was explored and in the process several developments were achieved and discoveries made. These included the use of inorganic bases under phase transfer conditions for the Heck reaction of acrylic acid as well as the synthesis and application of phosphine and phosphite ligands in the Heck reaction of acrylic acid esters. The successful use of low palladium loadings (as low as 0.01mol%) in the arylation of diethyl malonate using aryl chlorides and the application to the synthesis of ketoprofen and phenobarbital was demonstrated. The novel application of palladium catalysis to the arylation of methanesulfonamides and the first example of a bromoindole derivative as the aryl halide partner in an enolate arylation reaction was demonstrated. Ligand-free palladium catalysed phenylation of pinacolone followed by Baeyer Villiger oxidation led to a proposed novel synthetic route to tert-butyl esters of 2-arylacetic acids. The palladium and copper catalysed arylation of acetoacetate esters, with in situ decarbonylation, provided a different route to 2-arylacetic acid esters which are useful in the preparation of non-steroidal anti-inflammatory compounds

Synthetic studies on the C20 backbone of the fumonisins using chiral sulfoxides

Fusarium moniliforme is a common contaminant of maize, a basic staple of the diet of both humans and animals. The fungus is the causative agent of equine leucoencephalomalacia (LEM) and has been implicated in human oesaphageal cancer. The structure of the fumonisins, a family of structurally related mycotoxins isolated from cultures of F moniliforme responsible for LEM has been established. Thus fumonisin B1 is the diester formed by the Re carboxy group of propane-I, 2, 3-tricarboxylic acid with the C-14 and C-15 hydroxy groups of (2S,3S,5R, 1 OR, 12S, 14S,, l 5R, l 6R)-2-amino-12, 16-dimethyl-3,5, 10,- 14, 15-pentahydroxyicosane. Retrosynthetic analysis of the C20 backbone of fumonisin B1 by disconnection of the C-1 0-C-11 bond identifies 4,8-dimethyl-1,2,6, 7-tetrahydroxydodecane, synthon B and 7-amino-1,4,6-trihydroxy-octane, synthon C as the key intermediates in a proposed synthesis. The formation of the same bond in the synthetic direction is more demanding as it requires that the formation of the carbon-carbon bond generates at the same time a new stereogenic centre in a stereodefined fashion. The work described in this thesis investigates a strategy for the formation of the C-1 0-C-11 bond in the C20 backbone of fumonisin B1 with the concomitant introduction of the C-11 hydroxy group by employing chiral sulfoxide methodology. The methods used are based on the highly stereoselective reduction of J3-ketosulfoxides and the ability of the sulfoxide moiety to stabilise an a-carbanion in order to effect carbon-carbon bond formation by a nucleophilic substitution reaction. Various model compounds for parts of the C20 backbone were prepared to test the practicality of the outlined strategy. Both the synthesis of a number of chiral J3-ketosulfoxides and their stereoselective reduction were successfully completed. However, only limited success was achieved in the final carboncarbon bond formation reaction. From the results it became clear that an alternative strategy for carboncarbon bond formation using chiral sulfoxides is required and some possible strategies are discussed. During the course of this study a new method for the synthesis of chiral J3-ketosulfoxides from methyl ptolylsulfoxide and an aliphatic nitrile was developed. In addition an improved method for the synthesis of the synthon corresponding to the C- l -C-8 unit of the C20 backbone of the fumonisins is presented in the thesis.Dissertation (MSc)--University of Pretoria, 1997.ChemistryMScUnrestricte

Tetra­ethyl­ammonium tricarbonyl­chlorido­(pyrazine-2-carboxyl­ato-N 1,O)rhenate(I)

In the title complex, (C8H20N)[Re(C5H3N2O2)Cl(CO)3], the ReI atom is coordinated facially by three carbonyl groups; the bidentate pyrazine­carboxyl­ato ligand and a chlorine atom complete the distorted octa­hedral coordination

Antimicrobial Peptides: Their Role as Infection-Selective Tracers for Molecular Imaging

Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal host’s cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.National Research Foundation (NRF), the Institute of Cellular and Molecular Medicine and the Nuclear Technologies in Medicine and the Biosciences Initiative (NTeMBI), a national technology platform developed and managed by the South African Nuclear Energy Corporation (Necsa) and funded by the Department of Science and Technology (DST).http://www.hindawi.com/journals/bmrihb201

Tetra­ethyl­ammonium tricarbonyl­chlorido(quinoxaline-2-carboxyl­ato-κ2 N 1,O)rhenate(I)

In the title compound, (C8H20N)[Re(C9H5N2O2)Cl(CO)3], the ReI atom is coordinated facially by three carbonyl groups, the bidentate quinoxaline-2-carbaldehyde ligand and a chloride atom, forming a distorted octahedral geometry.. The crystal packing is controlled by C—H⋯O hydrogen bonding and π–π stacking inter­actions involving the benzene rings, with a centroid–centroid distance of 3.4220 (1) Å