School of Chemistry - Theses
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ItemThe oxidative damage of biological molecules by air pollutants NO2● and NO3●( 2019)Air pollution is perceived as the world’s greatest environmental risk to human health. According to the World Health Organization (WHO), air pollution is responsible for the deaths of about 7 million people each year. In the industrialised urban environment, nitrogen dioxide (NO2•) and ground-level ozone (O3) are the most oxidising air pollutants. Exposure to these gases has been associated with increased respiratory health problems, such as exacerbation of existing asthma and allergies. While the adverse health effects of air pollution are clear, the precise underlying mechanism through which the pollutants affect biological systems is not well understood. It has been speculated that nitrate radicals (NO3•), which are formed from the reaction of NO2• and O3, play an important role in the oxidative damage of biological systems. Therefore, this thesis explores reactions involving NO3• and biomolecules such as proteins through a combination of kinetic, computational and product studies, in order to gain a better understanding of the fundamental chemical pathways that lead to oxidative damage in biological systems upon exposure to air pollution. The first section of this thesis investigates the reaction of NO3• with aliphatic amino acids and peptides. From laser flash photolysis experiments, it was found that NO3• reacts with aliphatic amino acids and peptides at multiple sites through proton-coupled electron transfer (PCET) at the amide nitrogen, and hydrogen atom transfer (HAT) at the α-carbon or the activated C–H moiety (e.g., tertiary carbons) with the rate of about 1 x 10(6) M−1 s−1. Following the above finding, this thesis proceeds to examine the reaction of NO3• with aromatic amino acids and peptides. A faster rate by a factor of 5–6 suggests that the reaction occurs at the aromatic ring through electron transfer (ET). An unprecedented amide neighbouring group effect was discovered, by which the rate of aromatic ring oxidation is increased considerably when the ring is flanked by two amide groups, instead of one amide and one ester group. Due to this effect, phenylalanine can potentially act as a relay amino acid in a long-distance ET even though the aromatic ring in phenylalanine is not readily oxidisable under biochemical conditions. The third section of this thesis explores NO3• reactions involving proline, where its side chain is covalently bound to the α-amino group. This unique structure increases electron density at the nitrogen and significantly accelerates the rate of ET at this nitrogen by a factor of about 600 compared to the other aliphatic substrates. However, when the amide moiety in proline residue is involved in the amide neighbouring group effect, accelerating the rate of aromatic ring oxidation, the rate of ET at this nitrogen was found to decrease significantly. The final part of this thesis studies the reaction of NO2• with various biological molecules, including short peptide and cholesterol derivatives. It was found that contrary to the widely accepted radical pathway, the reaction of NO2• with these molecules involves an ionic pathway through the dissociation of N2O4 into NO+ and NO3−.
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ItemCoinage metal hydrides: reactive intermediates in catalysis and significance to nanoparticle synthesis( 2019)The coinage metal hydrides of copper, silver and gold have applications in catalysis and nanoparticle synthesis. Coinage metal hydrides are key intermediates in the chemical transformations of a range of substrates including fine chemical syntheses and chemical storage of hydrogen. Ranging from mononuclear coinage metal hydrides to clusters and nanoparticles, a fundamental understanding of their atomic and molecular interactions is invaluable in developing innovative solutions to practical problems. The reactive sites can be identified using a range of spectroscopic methods allowing the “tuning” and/or “reshaping” of the reactive site by ligands to control the reactivity. Mass spectrometry provides a means to identify coinage metal hydrides in solution and further allows isolation of discrete coinage metal hydrides that can be: (i) characterised, for example by spectroscopic methods, (ii) reacted with neutral substrates, or (iii) fragmented to generate reactive intermediates in the gas phase. The use of borohydride in nanoparticle synthesis is well-known. Chapter 2 describes a mass spectrometry directed synthesis to afford the first isolable silver hydride borohydride cluster, [Ag3(μ3-H)(μ3-BH4)L3]BF4 (L =bis(diphenylphosphino)methane), structurally characterised by X-ray crystallography. Gas-phase experiments and DFT calculations reveal ligand (L) loss from [Ag3(H)(BH4)L3]+ results in the loss of BH3 and a geometry change of the cluster to yield [Ag3(H)(BH4)Ln]+ (n = 1 or 2). This work reveals links between silver hydride/borohydride and silver hydride nanoclusters adding to our understanding of silver nanoparticle synthesis using borohydride salts. Chapter 3 examines that the reactivity of CO2 with the binuclear silver hydride cation core, [Ag2H]+, can be controlled by design. Reshaping the geometry and reaction environment of [Ag2H]+ using a range of phosphine ligands (bis(diphenylphosphino)methane, 1,2- bis(diphenylphosphino)benzene and bis(diphenylphosphino)ethane) allows “tuning” of the active site’s reactivity toward formic acid to produce H2. Gas-phase ion-molecule reactions, collision-induced dissociation, infrared and ultraviolet action spectroscopy and computational chemistry link structure to reactivity and mechanism. The gas-phase studies were then translated to solution-phase studies using NMR to show that H2 could be produced from solutions comprising well-defined ratios of ligand, AgBF4, NaO2CH and HO2CH at near ambient temperature. Chapter 4 further developed the concept of altering the reactive site by changing the binuclear metal centres of the [LAg2H]+ core to compare all six possible combinations of copper silver and gold i.e. [LAg2H]+, [LCu2H]+, [LAu2H]+, [LCuAgH]+, [LCuAuH]+ and [LAgAuH]+ in the gas phase. DFT calculations, gas-phase ion-molecule reactions and gas-phase energy-resolved collision-induced dissociation showed both metal centres play a role in the reaction with formic acid. One metal site functions as an “anchor” for an oxygen of formic acid or formate while the other facilitates the dehydrogenation step resulting in the formation of H2. It was found that the copper homobinuclear species performed best overall. Attempts to isolate the reactive intermediate [LAg2(O2CH)]+ by using a range of bisphosphine ligands resulted in the isolation of an unusual co-crystal in the case of L = dcpm as described in Chapter 5. Single crystal X-ray diffraction of crystals suitable for crystallographic analysis revealed two discrete tetranuclear silver clusters [(μ2-dcpm)Ag2(μ2-O2CH)(η2-NO3)]2·[(μ2- dcpm)2Ag4(μ2-NO3)4]. The solution-phase studies, tracked by NMR, show that H2 could be produced from solutions comprising well-defined ratios of ligand, AgBF4, NaO2CH and HO2CH at 65⁰C. Gas-phase studies indicate that while the tetranuclear cluster [L2Ag4(O2CH)3]+ undergoes sequential decarboxylation reactions, none of the resultant hydrides react with formic acid. These results highlight important role of the binuclear hydride [LAg2(H)]+ in the catalytic decarboxylation of formic acid. Hydrido cuprate [CuH2]- has been explored for its applications in hydrogen storage. Chapter 6 indicates two chemically induced routes for the liberation of hydrogen when [CuH2]- is reacted with various chemical substrates. One path occurs via homocoupling of both hydride ligands giving the substrate-coordinated copper, the other by protonation with acids.
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ItemTowards the synthesis of the emestrin family of natural products( 2018)A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.
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ItemA journey of synthetic chemistry towards immunogenic glycolipids and non-lipidic antigens( 2018)Microbes, both pathogenic and commensal, produce a wide range of glycolipids that act as unique molecular signatures. The ability of the human immune system to fight infection as well as to modulate commensal organisms are active areas of research. Microbial glycolipids are known to interact with the immune system though discrete protein families including CD1 and Mincle. The main challenge in the study of such systems is the difficulty in, and often impossibility of, obtaining pure, homogeneous material from natural sources. We synthesised four classes of molecules of both natural and unnatural origin to investigate their potential to modulate the human immune system through the CD1 and Mincle axes. Chapter 2 describes the synthesis of a range of cholesteryl α-glucosides that are found in members of the Helicobacter family, including the prominent gut bacterium Helicobacter pylori. As part of this work we investigated the effect of remote protecting groups on the sugar on the stereochemical outcome of glucosylation reactions. In chapter 3 we designed and synthesised a set of purely synthetic glycolipids drawing upon the structures of known Mincle agonists. We investigated these compounds for their ability to signal through Mincle as a prelude to the development of improved vaccine adjuvants that promote cellular and humoral immunity. Chapter 4 discloses the total synthesis of α-glucosyl and α-glucuronosyl diglycerides, found in both pathogenic and commensal organisms relevant to human health. Finally, we prepared a set of analogues of the unique, non-lipidic synthetic CD1d-restricted effector, PPBF, to explore structure activity relationships for T cell activation. In collaboration with immunologists, the synthetic glycolipids and non-lipidic antigens have been studied for their ability to activate CD1d-restricted natural killer T cells or for their ability to stimulate signalling through Mincle.
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ItemNew techniques for elucidating the degradation of modern paints using polyvinyl acetate as a case study( 2017)Conservation of modern art poses many challenges, which include the use and take up of new materials with untested ageing mechanisms. While recent work has established several analytical tools and techniques that can identify and characterise modern materials, further work is required to ascertain fundamental chemical degradation pathways of a range of artists’ materials. Polyvinyl acetate (PVAc) is one such material and is commonly used in the creation and conservation of art. Understanding how PVAc degrades over time is a problem of both fundamental and practical importance. This study explores tools available in polymer chemistry and applies these to conservation research in order to gain further insight into the degradation of PVAc. Computational chemistry techniques using ab initio and Density Functional Theory methods were applied to explore key degradation reactions of PVAc materials. First, benchmarking studies were performed to identify the most appropriate level of theory to use in this investigation. BHandHLYP/cc-pVDZ was identified as being the most suitable as it offered excellent agreement of results calculated with the high-level benchmark method, G3(MP2)- RAD, at a fraction of the computer costs. Second, hydrogen abstraction reactions using dimeric and trimeric units of PVAc with hydroxyl, peroxyl and t-butoxyl radicals were modelled. The results from this study indicated that hydrogen abstraction was very likely to occur at room temperature with energy barriers for abstraction by hydroxyl and t-butoxyl radicals being below 24 kJ mol-1 and 53 kJ mol-1 respectively. Main chain and side chain scission reactions were also modelled, however the energy barriers for these reactions were all in excess of 100 kJ mol-1 indicating that these reactions are unlikely to contribute greatly to the degradation of PVAc at room temperature. Accelerated ageing studies were applied to PVAc films so as to provide insight into the longterm behaviour of PVAc when subjected to heat and light. Profluorescent nitroxide techniques were trailed to monitor the free radical mediated degradation as many commonly employed analytical techniques lack the molecular sensitivity to monitor the onset of degradation within paint films. A perylene based profluorescent nitroxide was identified as most suitable for this application and was synthesized and used to monitor the degradation of solvent borne PVAc resins and two commercial PVAc dispersion products when exposed to four accelerated ageing conditions. While the first nitroxide with the water-based dispersion products presented issues of incompatibility, a novel water-soluble profluorescent nitroxide was synthesized and initial accelerated ageing studies were conducted using one of the commercial dispersion products. To elucidate further information regarding the chemical reactions that occur during degradation, 13C NMR spectroscopy was used to analyse selected PVAc resin and dispersion samples exposed to various accelerated ageing conditions, including samples aged for over five years. The results of this study demonstrate that both the computational chemistry and profluorescent nitroxide techniques are useful tools for degradation studies within conservation research. This study also indicates that PVAc is highly susceptible to free radical induced degradation. This finding provides a secure direction for much needed ongoing research to better help determine practical treatments required to ameliorate the impact of free radical species if important cultural material is to be saved for future generations.
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ItemOxidative and chemical modification of amino acids by nitrogen dioxide, ozone and the reactive paracetamol metabolite NAPQI( 2016)Oxidative damage has been implicated in a wide range of diseases including cardiovascular disease, diabetes, asthma, cancer and atherosclerosis. While this damage is typically caused by ROS or RNS generated in vivo, oxidative damage is also mediated by environmental and secondary oxidants such as NO2•, O3 and reactive drug metabolites. This thesis explores the fundamental reactivity of environmental and secondary oxidants towards model amino acids and peptides. According to the WHO, environmental pollution represents the single greatest environmental risk to human health. Exposure of NO2• and O3, common polluting gases, has been linked to the development of asthma, bronchitis, heart disease, stroke, cancer and COPD. While this link is clear, the precise molecular mechanism through which NO2• and O3 cause these adverse health effects is largely unknown. The first section of this thesis explores the reactivity of NO2•, O3 and NO3• towards model biomolecules. N-Acetyl and C-terminal methyl ester protected amino acids and peptides were treated with NO2•, O3 and NO3•. NO3• was generated in situ from the reaction of NO2• and O3 or from the UV irradiation of CAN. These model biomolecules are irreversibly damaged as a result of exposure. The reaction of NO3• generated from the UV irradiation of CAN yields β-nitrate esters from aromatic amino acids, while NO3• generated in situ generally yields nitration products. In the case of tryptophan, pyrroloindoline and nitrosopyrroloindoline products were obtained. Exposure of NO2• to phenylalanine, glycine, alanine and valine containing peptides was found to lead to an unprecedented modification, rearrangement and ultimate excision of amino acids in a peptide chain. The thesis proceeds to examine the fundamental reactivity of a secondary oxidant, the reactive paracetamol metabolite NAPQI. Paracetamol is one of the most widely used analgesic drugs in the world and overdose represents a significant burden on the health system. NAPQI, generated in high concentrations in the liver by CYP450 enzymes, is known to form protein adducts, which have been linked to the development of liver toxicity. The focus of many studies has been on the role of cysteine – paracetamol adducts, formed from the reaction of NAPQI with cysteine residues. In this work, the reaction of NAPQI with a range of amino acids (Cys, Tyr, Trp, His, Lys, Arg, Met, Gln, Glu, Ser and Val) was examined and it was found that NAPQI forms adducts with Cys, Tyr, Trp and Met. Novel paracetamol – amino acid adducts were isolated and characterised by spectroscopic methods. The final part of this thesis explores the reaction of aromatic amino acids and peptides with CAN under UV irradiation. This method was utilised to form β- substituted amino acids with high diastereoselectivity in a single reaction step. Method development was performed in an effort to improve the yield of the β- nitrate ester products. This included 1H NMR based reaction screening of N- terminal protecting groups, work-up procedure and reaction conditions. From these experiments, it was found that ideal reaction conditions included N-acetyl protection, evaporation in vacuo, an excess of CAN and dilute solution concentrations.
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ItemTowards valence tautomerism in polynuclear complexes( 2012)The synthesis, structural and physical characterisation of families of dinuclear cobalt complexes with the bridging bis-o-dioxolene ligands 3,3,3',3'-tetramethyl-1,1'-spirobis(indane-5,5',6,6'-tetrol) (spiroH4) and 3,3'-bis-2-hydroxy-1,4-naphthoquinone (bhnqH2) as well as dinuclear nickel complexes with N1,N2-bis(2-((E)-(3,5-di-tert-butyl-2-hydroxyphenylimino)methyl)phenyl)oxalamide (H4Ltert) and N1,N2-bis(2-((E)-(2-hydroxy-3,5-dimethylphenylimino)methyl)phenyl)oxalamide (H4Lmethyl) were undertaken, with an emphasis on investigating potential valence tautomeric (VT) behaviour. A new family of dinuclear cobalt complexes incorporating deprotonated spiroH4 and ancillary ligands derived from tris(2-pyridylmethyl)amine (TPA) was investigated. Systematically increasing the number of methyl groups at the 6-position of the pyridine arms of the ancillary ligand was shown to fine tune the charge distribution within each complex. Pure samples of [Co2(spiro)(TPA)2]2+ (12+), [Co2(spiro)(MeTPA)2]2+ (22+), [Co2(spiro)(Me2TPA)2]2+ (32+), [Co2(spiro)(Me3TPA)2]2+ (42+), [Co2(spiro)(TPA)2]3+ (53+), [Co2(spiro)(TPA)2]4+ (64+) have been isolated. In the solid state, crystallographic analysis, variable temperature magnetic susceptibility and X-ray absorption spectroscopy (XAS) data revealed 12+, 42+ and 64+ exist in the LS-CoIII-(spirocat-cat)4--LS-CoIII, HS-CoII-(spiroSQ-SQ)2--HS-CoII and LS-CoIII-(spiroSQ-SQ)4--LS-CoIII redox states, respectively, invariant of temperature (2-360 K). In solution, electrochemistry, electronic absorption and EPR spectroscopy analysis are consistent with the above assigned redox states, and also confirmed the presence of another redox state of LS-CoIII-(spiroSQ-cat)3--LS-CoIII in complex 53+. Due to spiroconjugation, electronic communication is observed across the spirocyclic carbon atom in the spiro ligand, which gives rise to weak antiferromagnetic coupling between the two halves of (spiroSQ-SQ)2- in 64+ and electron delocalisation across the ligand for (spiroSQ-cat)3- in 53+. The only complex to exhibit a temperature dependent charge distribution is 32+. Variable temperature magnetic susceptibility and XAS data are consistent with two transitions in the solid state occurring at around 100 and 300 K, whereas UV-visible absorption spectroscopy indicated that two transitions occur at 200 and 250 K in butyronitrile. Therefore, complex 32+ undergoes two thermally-induced VT transitions between LS-CoIII-(spirocat-cat)4--LS-CoIII and HS-CoII-(spiroSQ-cat)3--LS-CoIII and then to HS-CoII-(spiroSQ-SQ)2--HS-CoII. Evidence of a photo-induced VT transition was observed in the solid state at 10 K. Analogous to the spiro complexes, three new dinuclear complexes [Co2(bhnq)(MenTPA)2]2+ (n = 1 for 72+; 2 for 82+; 3 for 92+) with the deprotonated form of bhnqH2 were isolated. In the solid and solution states all three of these complexes existed in the HS-CoII-(bhnqQ-Q)2--HS-CoII redox state independent of temperature (2-300 K). Increasing the number of methyl substituents on the TPA ligand favours the stabilisation of HS-Co(II). An increase in distortion from octahedral coordination around each cobalt centre was correlated with the decrease in room temperature magnetic susceptibility due to quenching of the orbital contribution. A search for potential dinuclear nickel VT systems afforded two square-planar and two octahedral complexes: [Ni2(Ltert)] (10), [Ni2(Lmethyl)] (11), [Ni2(Ltert)(py)4] (12) and [Ni2(Lmethyl)(py)4] (13), where the metal is Ni(II). None of these complexes displayed evidence of a VT transition. Chemical (with (NH4)2Ce(NO3)6) and electrochemical oxidation of 10 led to the decomposition of the complex, giving N1,N2-bis(2(5,7-di-tert-butylbenzo[d]oxazol-2-yl)phenyl)oxalamide (14).
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ItemNovel fluorescent angiotensin AT1 receptor antagonists( 2012)Hypertension is a severe condition that affects many people worldwide. The pathophysiology of hypertension is unknown. Sartans (selective AT1 receptor antagonists) are known to be the most direct and widely used class of antihypertensive drugs that block the vasoconstrictive hormone angiotensin II from binding at its AT1 receptor. Since the discovery of Losartan (2), many drugs are clinically used today. Sartans display a diverse pattern of antagonism however there is some debate as to why this occurs. Some believe it’s due to the antagonist induced changes in the AT1 receptor conformation, others believe it’s due to the levels of cell surface receptor expression and internalisation of the antagonist-receptor complex. Binding of fluorescent sartans to AT1 receptors, will enable the investigation of AT1 receptor localisation. This will provide an insight of the molecular pharmacology of AT1 receptors in cell and tissue systems and in turn will provide a better understanding of the physiological mechanisms involved with the disease. With the aim of preparing fluorescent sartans for use in the study of the molecular pharmacology and cellular localisation of AT1 receptors in cell-based systems, initial work was thus directed towards the synthesis of a series of analogues 103 - 114 of Fonsartan (14), in order to explore the effect of heteroatom substitution and substituent size on the AT1 receptor binding ability of the sartans. The approach involved direct coupling of the common bromo-biphenyl scaffold 32 with several novel aryl-thio substituted imidazoles 90 - 95. Also prepared were coumarin analogues 151 and 152 of Fonsartan, which required synthesis of the novel imidazole 149. In addition, the coumarin analogue 176 of Losartan (2) was also synthesised. Pharmacological testing revealed that compounds 103 – 108, 109 – 114, 151 and 152 were potent AT1 receptor antagonists. The novel AT1 receptor antagonists synthesised in this project that have shown strong inhibition activity and possess fluorescence emission properties suitable for in vitro cellular imaging were sartans 106, 112 - 114, 151 and 152. The novel fluorescent angiotensin AT1 receptor antagonists 113, 114 and 176 showed weak inhibition activity. Results from the in vitro cellular imaging, using Chinese hamster ovary (CHO) cells stably expressing the rat AT1a receptor, revealed that the novel fluorescent sartans 106, 112 - 114, 151 and 152 were too lipophilic to observe the localisation of AT1 receptors in CHO cells. The synthesis of less lipid soluble selective AT1 receptor antagonists with appropriate fluorescence emissions useful for biological investigations may prove as useful tools for the investigation of cellular localisation and trafficking of the AT1 receptors both in vitro and in vivo.
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ItemSynthesis and biological analysis of novel Fluorine-18 positron emission tomography (PET) imaging agents for hypoxic tissues in tumours( 2012)The significance of imaging hypoxia with the PET ligand [18F]FMISO (1.1) has been demonstrated in a variety of cancers. However, as a result of the slow kinetics of [18F]FMISO (1.1), a 2 h delay between tracer administration and patient scanning is required. Labelled chloroethyl sulfoxides have shown faster kinetics and higher contrast than [18F]FMISO (1.1) in a rat model of ischemic stroke. However, these nitrogen mustard analogues are unsuitable for routine production and use in humans. Development of new PET imaging agents was achieved by attempting structural modifications of parent sulfoxides. Five novel radiotracers [18F]1.18, [18F]1.20, [18F]1.21, [18F]1.23 and [18F]1.25 representing various of structural modifications of the parent sulfoxide-based imaging agents were synthesized. These modifications included the introduction of the propargyl group, acetic ester group and trizole-ethyl group to the parent sulfoxides. Radiotracers [18F]1.18, [18F]1.20, [18F]1.21, [18F]1.23 and [18F]1.25 were successfully prepared (with RCY of 2.5%, 15%, 28%, 2.5%, and 3.5% respectively) from the corresponding precursor molecules 1.17, 1.19, 1.22 and 1.24 either via 2-[18F]fluoroethyl azide click chemistry or conventional nucleophilic displacement of a chloride leaving group. Radiotracers [18F]1.20 and [18F]1.21 were synthesized from a single precursor compound 1.19, utilizing both radiolabelling methods. In-vitro and in-vivo evaluation of radiotracers [18F]1.18, [18F]1.20, [18F]1.21, [18F]1.23 and [18F]1.25 were accomplished. Only radiotracer [18F]1.25 was stable in both mice and rat S9 liver fraction during phase I aerobic metabolism studies. Phase I aerobic metabolism studies of tracer [18F]1.20 and [18F]1.21 showed that both tracers were stable in mice S9 liver fraction but undergo metabolism in rat S9 liver fraction, with biological half-lives of 32.39 min and 43.32 min respectively. While, tracer [18F]1.23 underwent minor phase I metabolism in mice and rat S9 liver fractions. Imaging studies using an SK-RC-52 tumour model in BALB/c nude mice have revealed that [18F]1.23 is the most promising hypoxia radiotracer in the series. This tracer shown high t/m ratio of 3.3 in large sized tumours with a pO2 value less than 5 mmHg. Thus, [18F]1.23 has emerged as an exciting new lead compound for further development. Radiotracers [18F]1.18 and [18F]1.20 are also retained in hypoxic tissues at highly hypoxic condition and mildly hypoxic conditions respectively, showing different hypoxia selectivity. [18F]1.18 and [18F]1.20 has emerged as a promising new lead structure for further development of sulfoxide-based hypoxia imaging agents. In particular the mechanism of uptake needs to be elucidated and changes to the chemical structure need to be made in order to reduce metabolism and improve radiotracer kinetics. Whereas [18F]1.21 and [18F]1.25 are cleared from those tumours at a rate similar to that of muscle tissue, showing great promise in future development of hypoxic radiotracer. Investigation of new PET imaging agent with diazobenzene as a bioreducible functional group, replacing the sulfoxide moiety was achieved and radiotracer [18F]1.27 was synthesized from precursor 1.26 in RCY 6.6%. Radiotracer [18F]1.27 underwent metabolism in faster rate in rat liver fraction in comparison to mice liver fraction, with the biological half-life of [18F]1.27 being 118.5 min for rat S9 liver fraction, while the biological half-life in mice S9 liver fraction was calculated to pass the 2 h incubation period (139 min). The imaging studies of [18F]1.27 shows some promises as a platform for new development of hypoxia radiotracer. However, structure modification of this aniline yellow derivative needs to be undertaken to improve this derivative further towards hypoxia imaging agents.
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ItemConfined conjugation MEH-PPV derivatives: synthesis, photophysics and energy transfer( 2012)Conjugated polymers based on poly(2-methoxy-5-(2’-ethylhexyloxy)-1,4- phenylenevinylene) (MEH-PPV) have received considerable attention owing to their interesting luminescent and semi-conducting properties. The performance of optoelectronic devices based on conjugated polymers, such as organic light-emitting diodes (OLEDs) and organic photovoltaic devices (OPVs), is predicated by an understanding of energy transfer processes occurring within and between polymer chains. Despite the large body of knowledge accumulated over the last twenty years, there remains a need to develop an energy transfer model capable of describing the observed fluorescence properties of MEH-PPV. The purpose of this thesis is to explore the photophysics and energy transfer dynamics of well-defined MEH-PPV oligomers and pendant polymers. These materials allow for the establishment of structure-property relationships, and serve as models for understanding the fluorescence properties of MEH-PPV. A series of MEH-PPV oligomers, ranging from 3 to 5 repeat units, was prepared using Horner-Wadsworth-Emmons chemistry from readily synthesised precursors. The oligomers displayed the expected red-shift in absorption and emission maxima as conjugation length increased. Fluorescence quantum yields and fluorescence lifetimes decreased in the order trimer > tetramer > pentamer, owing to increases in the rates of both radiative and non-radiative processes. The non-mirror image relationship between absorption and emission spectra, also observed in MEH-PPV, was investigated using a number of techniques. X-ray crystallography on n-hexyl derivatives, synthesised via a similar route to the MEH-PPV oligomers, showed that the oligomers adopted twisted helical conformations in the ground state, with dihedral angles of ~7° measured for the MEH-PPV trimer. MM2 calculations on a methoxy substituted trimer indicated that a family of conformers was likely to exist in room temperature solution. Temperature dependent absorption and fluorescence measurements provided additional evidence for the presence of non-isoenergetic torsional isomers in the ground state. The rate of conformational relaxation in the excited state was measured using ultrafast transient absorption spectroscopy on the MEH-PPV tetramer and pentamer, with relaxation times of 4 and 5 ps obtained, respectively. Luminescence measurements in neat films and in PMMA matrices demonstrated aggregation occurred in the solid state. Pendant polymers consisting of short MEH-PPV segments (from 3 to 5 units) attached to a non-conjugated poly(styrene) backbone were prepared using a post-polymerisation functionalisation approach. This method involved RAFT polymerisation of vinylbenzyl chloride, followed by a series of post-polymerisation modifications. The final polymers possessed narrow polydispersities (1.08 for each), and molecular weights ranging from 10100 to 17500 g/mol. The absorption and fluorescence profiles of the polymers redshifted as side-chain conjugation length increased. The non-mirror image relationship between absorption and emission spectra was attributed to absorption by a population of side-chain torsional isomers, followed by geometry relaxation to more planar structures prior to emission. Fluorescence decays were modelled using a double-exponential function, although this most likely approximated more complex decay behaviour. Thin film measurements provided evidence for aggregation in the series, with red-shifting of the [0,0] band observed in the neat film emission spectra. Energy transfer in the series was investigated using fluorescence polarisation measurements, and was found to be highly efficient. A Förster resonance energy transfer model was applied for describing energy transfer dynamics between adjacent chromophores, giving rates in the order of 1012 s-1. Pendant polymers labelled with low band-gap acceptors were also investigated. A statistical donor-acceptor polymer consisting of 15 trimer donor chromophores for every pentamer acceptor was prepared by a post-polymerisation functionalisation approach. Photophysical measurements indicated that energy transfer occurred with an average efficiency of 85%. A pendant polymer bearing a terminal perylene diimide (PDI) end-group was also prepared. This synthesis required the use of a PDIfunctionalised RAFT agent, followed by post-polymerisation functionalisation to attach the tetramer donor chromophores. This system was found to undergo electron transfer following selective excitation of the tetramer donors. The relative HOMO/LUMO levels were determined for the model poly(tetramer), and found to be conducive for electron transfer to PDI. The synthesis and solution photophysics of a water-soluble polymer were also explored. Water solubility was conferred by functionalisation of each pendant trimer chromophore with a PEG-3 group. This polymer adopts an aggregate structure in aqueous solution and intermolecular energy transfer between this polymer and an encapsulated MEH-PPV pentamer acceptor was demonstrated