Bio21 - 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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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.