School of Chemistry - Theses
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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.