Abstract: Herein, we report the synthesis of new chiral hydroxamic acid ligands for the V-catalysed asymmetric epoxidation reaction in aqueous solution. During the course of this project, a wide range of allylic alcohols were epoxidised under mild reaction conditions. The target epoxides were isolated in good-to-excellent yields with up to 94% ee. To further develop the project, we also report that the range of substrates has been extended to unfunctionalised alkenes. These materials have been successfully converted to the corresponding allylic alcohols in the presence of SeO2 and acetic acid. Asymmetric epoxidation was then achieved under anhydrous conditions in good-to-moderate yields with up to 76% ee and in certain cases, the overall transformation can occur as a one-pot process. A brief investigation into the development of organocatalytic transfer hydrogenation mediated by chiral pyridines has also been carried out. In this project, a range of chiral quarternary ammonium salts have been prepared as precursors to the corresponding dihydropyridines. It was our initial intention to utilise these chiral dihydropyridines in the enantioselective reduction of imines. This would result in the formation of the desired chiral amine and a quaternary pyridinium salt, which could then be reduced to reform the dihydropyridine in a catalytic cycle. However, with all pyridinium salts formed we were unable to produce the target dihydropyridines and this project was consequently abandoned.

In this work, force fields were developed to model flexible helical metalorganic framework solids (MOFs). Since no suitable force fields to model flexible MOFs had been reported, the study began by benchmarking an existing organic force field, CHARMM22, against Ni3(BTC)2(pyridine)6(4,5octanediol) 3. CHARMM22 force filed did produce a framework that retained its original threedimensional structure for the duration of the simulations, and did so at experimentally relevant temperatures provided a minimum number of 20 solvent molecules per unit cell were included. However, important inadequacies were found between the experimental crystal structure and the simulated one. Therefore a series of refinements of the force field were performed. The three best modified force fields were then used to simulate this MOF and a detailed analysis of its physical properties produced. A key conclusion from the development and testing cycle was that hydrogen bonding between the BTC and the hydroxyl groups of both the solvent and the framework alcohol molecules played a critical role in stabilizing the MOF. The transferability of these forcefields was tested against two new MOFs, for which experimental crystal structures had been reported: Ni3(BTC)2(pyridine)6(2,3butanediol) 3 (called MOF4) and Ni3(BTC)2(pyridine)6(1,2,6hexanetriol) 3 (called MOF6). One forcefield was found to give a good description of MOF4. For MOF6 however, competition for framework bonding between the diol and terminal hydroxyl group on the hexanetriol destabilized the framework with all three force fields. A stable MOF was produced only when the NiOT bond lengths were constrained to the experimental values. It was concluded that polarisation of ligand donor atoms by the Ni2+ needed to be incorporated in any future refinements of the forcefield. Finally, this study showed that the Ni3(BTC)2(pyridine)6(4,5octanediol) 3 MOF can display enantioselective properties. Solvent alcohol molecules of the same enantiomeric form as that incorporated into the framework were found to interact much more strongly with the framework than their enantiomer, and even formed enantiomer specific hydrogen bonds with the framework. Structural differences were also observed in solventBTC, solventNi and solvent pyridine geometries.

Fluorescent ligands have found numerous applications for studying interactions of drug molecules with their target and as a probe of biological systems. A common approach when designing and synthesising a fuorescent ligand is to separate the fluorophore and pharmacophore via a linker. One novel approach is to utilise click chemistry to allow the coupling of fluorophore to a pharmacophore. This thesis reports the results of an investigation into utilising click chemistry, specifically the alkyne-azide copper (I) cycloaddition to synthesis novel fluorescent GPCR ligands. Targets included the β1, β2 adrenoceptor and the muscarinic M3 receptor. Investigations into the introduction of a 1,2,3-triazole within the linker to the fluorophore resulted in 14 novel fluorescent antagonists active at the β1 and β2 adrenoceptor. The most promising ligand had log Ki values of -6.77 ± 0.20 (β1) and -7.32 ± 0.05 (β2). These ligands were used in a confocal microscopy studies to visualise the β1 and β2 adrenoceptors on the surface of CHO cells. However the ligands internalistion, and receptor visualisation was not possible. A range of structural modifications were made to reduce this with the introduction of a polar linker but this did not reduce the intracellular accumulation. The change to a longer wavelength fluorophore stopped intracellular accumulation but reduced the binding log Ki to - 5.16 ± 0.06 (β1) -5.96 ± 0.20 (β2). Twenty two novel fluorescent M3 ligands were synthesised and their inhibitory properties were investigated. An initial screen showed four promising ligands and further study into the binding affinities showed the ligands to have high potency (log Kb -7.97 ± 0.07 to -8.89 ± 0.11). These ligands were studied with confocal microscopy and intracellular accumulation did not occur. Structural changes to include a polar side chain or a sulfonic acid onto the fluorophore were investigated and led to three novel fluorescent ligands that had reduced lipophilicity. With this reduced lipophilicity, binding affinities were also reduced by ten fold compared to the original fluorescent ligand. The seven ligands were fully profiled physiochemically and kinetically. The physioschemical properties of these seven ligands gave a wide variety of lipophilic values. The kinetic profiles of the ligands exhibited very similar dissociation properties to those of the parent ligand with varying association rates. The Muscarinic M3 ligands synthesised show great binding affinities for fluorescent ligands and kinetic profiles that are extremely similar to the parent ligand. These fluorescent ligands hold characteristics that can be used to further examine the pharmacology of muscarinic receptors and be used to replace radioligands for binding studies.

The coordination chemistry of the rigid, aliphatic triamino ligand \(cis,trans\)-1,3,5-triaminocyclohexane (\(trans\)-tach) is investigated. With closed shell transition metals, \(trans\)-tach forms 1-D {Ag(OTf), ZnCl\(_2\)} networks and a 3-D {AgNO\(_3\)} coordination polymer with unprecedented topology. Coordination to the open shell transition metals {NiCl\(_2\), Ni(NO\(_3\))\(_2\), Cu(NO\(_3\))\(_2\), CuBr\(_2\), CuCl\(_2\), CuF\(_2\), CuSO\(_4\)} leads to discrete diligand complexes. Protonation of the copper(II) complexes predominantly forms monoligand species, which can aggregate into higher nuclearity clusters. Protonated Cu(NO\(_3\))\(_2\) and CuBr\(_2\) complexes (HNO\(_3\) and HBr, respectively) remain mononuclear. CuCl\(_2\) and CuBr\(_2\) complexes protonated with HCl, however, form trinuclear species comprising trigonal planar \(\mu_3\)-chloro ligands that aggregate into 1-D trinuclear copper(II) chains via hydrogen-bonded interactions. Protonated CuF\(_2\) forms a tetranuclear cubane type structure that aggregates into a 3-D nanoporous network via hydrogen-bonded interactions. Protonation of the CuSO\(_4\) diligand complex maintains the diligand coordination, forming a 1-D nanoporous network through hydrogen-bonded interactions. Coordination to square planar palladium(II) ions forms all possible coordination motifs (‘Tail’ = monodentate, ‘Head’ = bidentate coordination). ‘Head-to-Head’ coordination results in diligand complexes, ‘Head-to-Tail’ coordination forms cyclic hexanuclear structures and ‘Tail-to-Tail’ coordination leads to a trinuclear species. Extension of \(trans\)-tach via Schiff base formation with pyridine-2-carboxaldehyde results in a hexadonor ligand suitable for metal coordination. Depending on the stoichiometry of the metal, mono- or polynuclear complexes are formed.

The work presented in this thesis describes routes to the controlled growth of small polyoxometalate clusters achieved by utilising a range of organic counterions in conjunction with electrophilic Ag(I) ions. The subsequent isolation of a new building block; {Ag(β-Mo8O26)Ag} has demonstrated how subtle control can be achieved through the use of bulky and flexible counterions and by solvent. Within most structures the electrophilic ions form {Ag2} dimer groups that link together β-octamolydbdate anions to produce a family of structurally related architectures ranging from isolated units, one- and two-dimensional architectures. Each of the architectures contain {Ag(β-Mo8O26)Ag} based building blocks that can be controlled in their self-assembly by cation and solvent interaction in the solid state. This set of architectures differ in the coordination modes of the linker {Ag2} groups and in the nature of the Ag.Ag interactions that are present in most structures. Furthermore, the isolation of polymeric structures exclusively through solvent ligation has yielded one- and two-dimensional architectures where acetonitrile molecules in particular have formed pseudo cations around the {Ag(β-Mo8O26)Ag} based building blocks. The above synthetic strategy was also extended to other metals to yield some additional structures. Several of the silver polyoxomolybdate compounds have been further investigated on silicon substrates using Scanning Electron Microscope (SEM), and in some instance with Energy Dispersive X-ray (EDX), Transmission Electron Microscopy (TEM) and Selective Area Electron Diffraction (SAED). These techniques have revealed the growth of nanostructure on multiple length scales. Knowledge of the molecular architecture has given a unique understanding of the assembly of these nanostructures including various one-dimensional assemblies (nanorods and nanowires), that have been obtained through different, efficient and inexpensive synthetic methods. The structures have been identified and a hypothetical mechanism for the growth of Ag(0) based nanowires has been correlated to the partial oxidation of methanol and the reduction of Ag(I).

Of the numerous l3-blockers clinically available to treat conditions such as angina pectoris, hypertension and heart failure, none possess antagonist activity specific to the beta1-adrenoceptor. Those described as 'cardioselective', such as nebivolol and bisoprolol, generally show less than 50-fold beta1/beta2-selectivity, which can be lost at higher doses. Others, such as propranolol and sotalol are actually more beta2-selective. Overall, a degree of concomitant beta2-adrenoceptor blockade (risking compromised respiratory function and loss of peripheral vasodilatation) by current therapeutic agents precludes their use in patients with disorders such as asthma and peripheral vascular disease. This project aims to develop novel molecules with much improved beta1/beta2-selectivity over current beta1-blocker therapy as well as improving knowledge of ligand-receptor interaction at the beta1-adrenoceptor, through an analogue-based drug discovery approach. A highly selective or specific beta1-adrenoceptor antagonist is likely to cause fewer side-effects and be suitable for use in previously contraindicated disease states. This thesis reports the design, synthesis and pharmacological data (provided by Dr. Jillian Baker) of a library of novel ligands for the beta1- adrenoceptor, based upon the lead compound LK 204-545. LK 204-545 was selected based on reported high potency at the beta1-adrenoceptor as well as good beta1/beta2-selectivity. Modification of various motifs on structures derived from LK 204-545 allowed the generation of new structure-activity relationships and ultimately afforded the highly 131-adrenoceptor selective compound, 1-(2-(3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-2-hydroxypropyl amino)ethyl)-3-(4-hydroxyphenyl)urea hydroformate (12Sc). This compound acted as a highly-selective beta1-adrenoceptor antagonist in a pilot in-vivo study in the regional hemodynamic rat model (carried out by Prof. Sheila Gardiner).

Aryl Hydrocarbon Receptor (AhR) mediates drug and toxin action. The AhR proteins have been characterised in several mammalian species, and are soluble proteins found in various tissues. The AhR is normally found in the cytoplasm in a complex with 90 KDa heat shock protein (hsp90) and cellular chaperones such as ARA9 (AIP or XAP2) and p23. However, there has not been a systematic analysis of the proteins which chaperone the AhR ligand-binding domain (LBD). This work investigates the interaction between ligands and the AhR, the protein composition of the AhR ligand-binding domain (LBD) complex, by establishing translation of AhR LBD in reticulocyte lysate, which contains molecular chaperones such as hsp90, and p23 that stabilise the ligand binding form of AhR. EGFP (Enhanced Green Fluorescent Protein) has been coupled to the mouse AhR b-1 LBD, to enable fluorescence analytical techniques of ligand-binding to the AhR. The Glutathione S-Transferase (GST) affinity tag was fused to EGFP (GST-EGFP), then fused to AhR.LBD with one or two EGFP (GST-EGFP-AhR.LBD and GST-EGFP-AhR.LBD-EGFP) to enable rapid one-step purification of AhR fusion proteins, and associated chaperone proteins. Proteins were expressed in E.coli (BL21(DE3)plysS). The GST protein is soluble, and not fluorescent, and GST-EGFP and GST-EGFP-AhR.LBD-EGFP was soluble and fluoresecent. The GST-EGFP-AhR.LBD was an insoluble fluorescent protein. Thus, the AhR proteins were purified from bacteria to test the specificity of the pulldown system under conditions which do not yield functional Ah Receptor. The tagged AhR constructs were translated with [35S]-methionine in reticulocyte lysate and translation products were ~36, 66, 84 and 109 kDa on SDS-PAGE. Reticulocyte lysate programmed with GST-EGFP-AhR.LBD and GST-EGFP-AhR.LBD-EGFP both bound ~800 d.p.m 2,3,7,8-[1,6-3H]tetrachlorodibenzo-p-dioxin (a ligand for the AhR), while lysate programmed with GST.EGFP showed binding of ~15 d.p.m, indistinguishable from unprogrammed lysate. The AhR proteins were purified from reticulocyte lysate and subsequent pulldown experiments will enable proteomic analysis of the proteins associated with the AhR LBD.

Chapter 1 presents a review of the background and current research regarding Schiff-base olefin polymerization catalysts, with special reference to the salicylaldimine species. An attempt is made to review trends within the current literature. Chapter 2 describes the synthesis and polymerization properties of tetradentate ligands with a bibenzyl backbone at titanium and zirconium centres, prepared with the intent of sterically hindering a 1,2-Migratory Insertion into the ligand imine functionality. A custom-built polymerization reactor was used to determine the stability of the catalytic systems. Steric protection is moderately successful in enhancing the stability of these systems. Chapter 3 reports the synthesis and detailed polymerization behaviour of a series of group 4 catalysts based on salicyloxazoline ligands, which should be resistant to 1,2-Migratory Insertion. Comparisons are made between polymerization under different conditions, including using High-Throughput methodology to screen catalysts under a range of differing conditions rapidly. Such systems are extremely active for polymerization of ethene, but demonstrate limited stability at elevated temperature. Chapter 4 presents our investigations into the polymerization behaviour of salicyloxazoline catalysts containing a para-methoxy substituent on the phenoxy donor unit. This substituent significantly enhances the stability of the catalysts at elevated temperature. Chapter 5 explores the nature of the active species in polymerizations with group 4 salicyloxazoline species. Alkyl cations of such species are generated from metal alkyl species with borate activators, and also from metal chloride species with MAO. We conclude that the primary deactivation mechanism is loss of ligand to aluminium co-catalyst, and that the methoxy substituent prevents this. A computational approach (DFT) is also applied, to examine the catalytic pathways which may be available to various stereoisomers of the catalyst. Chapter 6 details the experimental procedures used during this work.

No description available.

No description available.