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Thesis submitted in fulfilment of the requirements for the Degree of Master of Technology: Organic Chemistry, Durban University of Technology, 2011. / Malaria, the most prevalent parasitic disease, is considered a neglected disease owing to insufficient research and development in synthesis and therapy worldwide. Therapy failures are frequent and are due to a variety of factors such as the intrinsic characteristics of the disease, conditions of transmission, and the difficult control of spreading through tropical areas. Primary factors are the complexity of the parasite life cycle and the development of drug resistance. Another critical factor is the increasing number of immune-compromised patients that suffer from malaria and human immunodeficiency virus (HIV) co-infections. Most of the drugs currently available to treat malaria are quinoline derivatives modelled on the quinine molecule, found in the bark of Cinchona trees. Over the last 50 years the use of quinine has declined owing to the development of synthetic 4-aminoquinolines such as chloroquine. However, the malaria parasite is rapidly becoming resistant to the drugs currently available. Recently bisquinoline compounds were found more potent than chloroquine against both chloroquine-sensitive and resistant strains of malaria; this improved efficacy and prompted an increased interest in the design of these anti-malarial drugs. Although several synthetic methods are available to synthesise bisquinolines, we report the synthesis of bisquinolines from simple, readily available and cost- effective starting compounds. The synthesis was accomplished in four reaction steps using the Claisen condensation, Vilsmeir-Haack reaction, formation of a Schiff base and thermal cyclization, sequentially. We used a conventional energy source and microwave irradiation for the synthesis, wherever possible, of 2, 4-dichloro-3, 4'-biquinoline and 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline. In the first step, 3-acyl-2, 4-dihydroxyquinoline is synthesised from an equimolar mixture of methyl-2-aminobenzoate and ethyl acetoacetate by microwave irradiation for 3 minutes; the yield is 90 % whereas by 6 hours refluxing the yield is 75 %. This is followed by the synthesis of 3-chloro-3-(2,4-dichloroquinolin-3yl) acrylaldehyde, by combining DMF and POCl3 at 00C to form the electrophile which reacts with 3-acyl-2,4-dihydroxyquinoline under microwave irradiation for 5 minutes; the yield is 65 % whereas by 6 hours refluxing the yield is 50 %. In the next step, several protocols to prepare a Schiff base 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene aniline are investigated with the best yield of 75% obtained by microwave irradiation for 5 minutes. Subsequently three aniline derivatives viz, 4-methoxyaniline, 4-chloroaniline and 4-methylaniline, are used as substrate to prepare 3-chloro-3-(2,4-dichloroquinolin-3-yl) allylidene-4-methoxyaniline, 3-chloro-3-(2 ,4-dichloroquinolin-3-yl) allylidene-4-methylaniline and 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene-4-chloro aniline at 68, 78 and 64 % yield, respectively. In the final step, 2, 4-dichloro-3, 4'-biquinoline is prepared; several methods were investigated, however, the best yield is 24 % which is obtained under alkaline conditions in the presence of K2CO3 and DMF by microwave irradiation for 10 minutes. The 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline derivative is also prepared in 18 % yield under the same alkaline conditions. The outline of the total synthesis of bisquinoline is presented graphically below. / National Research Fund.

In order to understand glycoprotein biosynthesis and processing, we have studied the glycosylation and intracellular assembly kinetics of murine IgM which are expressed functionally only at specific stages of B-cell differentiation by the corresponding tumor cell lines. We have shown that the majority of carbohydrate chains on intracellular IgM contain predominantly Man₈GlcNac₂ rate limiting step in the carbohydrate processing is the transport from the RER to the Golgi apparatus. We made comparisons of carbohydrate structures on secretory and membrane-bound u chains produced by different cell lines. Our results show that the carbohydrates on WEHI231 membrane-bound IgM are less processed, and the processing at individual glycosylation sites is different for IgMs produced by plasmacytoma (MOPC104E) and hybridoma (MPC11xW279.2) cell lines. In addition, we also show that the glycosylation and processing are dramatically altered by lowering the glucose concentration in the cell culture medium. These results are a beginning for our understanding of the influence of the polypeptide on the final glycosylation patterns of a glycoprotein, and the genetic and environmental control over the carbohydrate processing during intracellular transport. The kinetic studies on IgM synthesis and maturation in WEHI231 as well as WEHI279.1/12 cells have led to the conclusion that membrane bound IgM and soluble IgM are segregated and processed individually even in the same cell. These differences appear to lead to the changes in carbohydrate/processing for membrane-bound and soluble IgM.

A diblock copolymer of Poly (Styrene-b- [ethylene-co-propylene]) has been used as a stabilizer in non-aqueous dispersion polymerizations of methyl methacrylate and vinyl acetate in n-heptane. The particles thus produced were stabilized by well defined surface layers of ethylene-propylene copolymer chains. The dependence of the particle size on the stabilizer, monomer and initiator concentrations was studied. Both seeded and one-shot polymerization techniques were investigated. Polymer particles were characterized by transmission electron microscopy to determine particle shape and size. The long term stability of both types of polymer particles suggests that the anchoring efficiency in both systems was good. Rheological studies confirmed the sphericity of the particles and showed the particles to be non-flocculated under shear. The thickness of the surface layer was determined from viscosity studies of the dispersions at 298, 308 and 318K. Solution viscosities dispersions at of a narrow distribution standard of ethylene-propylene copolymer in n-heptane and in a binary liquid mixture of n-heptane and n-propanol (79:21, v/v) at 298, 308 and 318K were obtained in order to estimate the root-mean-square end-to-end distance of free ethylene-propylene copolymer chains. The thickness of the surface layer was observed to increase on raising the temperature and to decrease on changing the solvency of the dispersion medium from a good solvent to almost a theta solvent for the ethylene-propylene copolymer chains. The dimensions of the surface layer were slightly larger than the dimensions of the free ethylene-propylene copolymer chains in solution suggesting that long ethylene-propylene chains terminally anchored at the interface are only slightly extended over random coil dimensions. Calculations of the mean separation distance between adjacent stabilizing ethylene-propylene copolymer chains indicated close-packing of ethylene-propylene copolymer chains at the particle-liquid interface which may contribute to the slight extension of the ethylene-propylene copolymer chain conformation. The theta-conditions for ethylene-propylene copolymer in a mixture of n-heptane and n-propanol were determined using samples obtained by hydrogenating polyisoprene standards. The solvency of the dispersion medium for the stabilizing ethylene-propylene copolymer chain on the polymer particles was reduced until flocculation occurred, and this was achieved by cooling the dispersion system to find the critical flocculation temperature or by adding a non-solvent (n-propanol) for the ethylene-propylene copolymer chains at constant temperature to find the critical flocculation volume. The polymer dispersions just retained stability at theta conditions and started to lose stability when the dispersion medium was changed to slightly worse than a theta system for the ethylene-propylene chains. The close correspondence of the flocculation conditions to the theta conditions for free ethylene-propylene copolymer chains confirms that the steric stabilization mechanism is operative for these dispersions.

Butadiene trapping experiments demonstrated that the silylenoids, :SiMeCl and :SiC12, are intermediates in the Direct Synthesis. It is believed that two types of silylenoid are formed on the metal surface. One type reacts on the surface with methyl chloride to generate methylchlorosilanes. The second type is released from the surface where as the free silylene it may be trapped by butadiene; it is not important in methylchlorosilane production. The gas phase reaction between the silylenes, :SiMeX (X=Me,Cl) and :SiCl2, and halomethanes involves two parallel series of reactions: silylene insertion reactions and radical chain reactions. In the reaction between :SiMe2 ch1orofluorocarbons (CFCs) an efficient chain sequence dominated; the driving force being the formation of Si-Cl bonds. The radical chain initiation step is believed to involve the dissociation of a singlet silylene-CFC acceptor complex bound through chlorine to produce haloalkyl (major chain carrier) and ClMe2Si. radicals. Fluorine was never abstracted. The major cyclic adduct produced when :SiMeX (X=H,C1,Me) is trapped by butadiene, is the result of a 1,3-silyl shift in the initial vinylsilacyclopropane, not Si-C bond rupture. Silacyclopropanes containing a Si-H bond undergo a rapid reversible ring-opening 1,2-H shift generating an alkylsilylene. Thermolysis of 1,1-dimethylsilacyclopent-3-ene produced 1,1-dimethylsilacyclopent-2-ene, butadiene, and :SiMe2 via a non-concerted mechanism involving a vinylsilacyclopropane intermediate. Computer modelling demonstrated that no single reaction is rate-determining with all intermediates in a steady-state. Alkene elimination from 1-allyl-1-silacyclopent-3-enes involves a conformationally enhanced endocyclic retro-ene reaction generating a 2H-silole, followed by a fast 1,5-H shift giving a 1H-silole. When the allyl group is substituted, it isomerises via a 1,3-silyl shift. a-Aryl-chloromethylsilanes, ArMeXSiCH2Cl (X=H,Me), underwent isomerisation in the gas phase as a result of H?C1 exchange when X=H, and Ar?Cl exchange when X=Me. H?Cl exchange is believed to involve an 'inverse ylide', whereas Ar?Cl exchange is believed to be concerted, i.e. a dyotropic rearrangement.

A series of studies were undertaken directed towards the synthesis of taxinine. As part of these studies the need arose for a stepwise synthesis of a highly substituted butadiene from an aldehyde. The initial approach used the Peterson elimination to control the regio-chemistry in the formation of tri- and tetra-substituted dienes. The generality of this method appeared to be hampered by the basicity of 2-lithio-2-trimethylsilyl propane, which was required to undergo nucleophilic attack at an aldehyde. A study of the Diels-Alder reactions of a 3-alkyl-2,4-penta-l,3-diene and a 3-alkyl-4-methyl-penta-1,3-diene showed the former to react more efficiently. A deuterium labelling experiment eliminated the degeneracy of this diene in a 1,5-hydrogen shift as a reason for its increased reactivity. A more reliable route to the preparation of highly substituted butadienes was attained using the highly nucleophilic 2-lithio-2-phenyl- seleno-propane reagent. This route was used to prepare a triene system which underwent an intramolecular Diels-Alder reaction to enable the preparation of the taxane model compound 8,12,15,15-tetra- metllyltricyclo[9. 3. 1 .03,8] pentadec-ll-en-2-one which has the same stereochemistry and methyl group substitution as the naturally occurring taxanes. Attempts were then made to prepare taxinine using a carbohydrate derivative. A key step in the route to taxinine involved a Robinson annulation of a carbohydrate derived ketone. Alkylations of a carbohydrate derived enolate were studied initially. The Robinson annulation was then carried out using 3-trimethylsilyl-3-buten-2-ol and the enolate derived from methyl 4,6-O-benzylidene-3-deoxy-3-C- methyl-D-arabino-hexapyranosid-2-ulose.

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In view of the rapidly growing interest in P2Y receptors and the lack of subtype selective ligands, especially antagonists, the aim of this study was to evaluate novel ligands of P2Y receptors. This was performed using putative P2Y-selective antagonists reviewed in the literature and by designing and synthesising novel peptide ligands. Bovine aortic endothelial (BAE) cells that co-express P2Yl and P2Y2 receptors and ECV304, a human cell line were used for this study. ECV304 were evaluated as a suitable model for studying P2Y receptor pharmacology using currently available agonists and antagonists in assays of second messengers. Results showed that ECV304 cells express two P2Y receptors, a P2Y2-like receptor and a P2Y11-like receptor. During the study doubt was cast as to the origin of the human cell line ECV304. It was thought that these cells had spontaneously transformed from human umbilical vein endothelial cells. In this study it was clearly demonstrated that ECV304 cells shared the same DNA fingerprint as T24/83 bladder cancer epithelial cells and were indeed not endothelial in origin. However, ECV304 cells are human cells natively expressing P2Y receptors and are a very useful research tool for studying P2Y receptor pharmacology. Reactive blue 2 is a P2 receptor antagonist, but it is not subtype-selective, having effects at both P2X and P2Y receptors. A recent study showed that derivatives of reactive blue 2: acid blue 129, acid blue 80, acid blue 25 and acid violet 34, are P2Y- versus P2Xselective. These four derivatives have been investigated in this study for their relative selectivity at P2Y1 versus P2Y2 receptors using stimulation of inositol phosphate turnover in BAE cells as a measure of activity. Acid blue 25 failed to antagonise either the P2Y1 or the P2Y2 receptor. The other three compounds were shown to be weak antagonists that were not subtype-selective and had activity that was not truly competitiveNovel peptide ligands have been designed to mimic extracellular domains of the human P2Y2 receptor. Surprisingly, these novel mimetic peptides had "agonist-like" properties. Peptides alone directly activated second messenger production in bovine aortic endothelial cells and ECV304, and also augmented agonist responses in ECV304 cells. Interestingly, analogues of mimetic peptides were also capable of enhancing sub-maximal doses of natural agonists in ECV304 cells. These findings represent a unique action of mimetic peptides as they have effects at nonpeptide P2Y receptors. These observations indicate an important role of extracellular domains, particularly the third extracellular loop, in signal transduction by P2Y2 receptors. Furthermore, the "agonist-like" activity of P2Y2 receptor mimetic peptides has important implications for the study of P2Y receptor activation and may have therapeutic potential e. g. in the treatment of cystic fibrosis. Finally, these findings may be equally applicable to the design of allosteric modulators of other G protein-coupled receptors

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