Targeted molecular probes for investigating biological redox processes

This thesis explores molecular probes for understanding redox biology and oxidative stress. It is divided into eleven chapters and a reference section. The first two chapters comprise the general background of mitochondria, oxidative stress and strategies for targeting bioactive molecules to mitochondria (Chapter 1) and to the extracellular environment (Chapter 2). The work presented in Chapters 3-5 includes the synthesis of extracellulary-targeted antioxidants (ExCell antioxidants) in the University of Glasgow. The targeting strategy is novel and was confirmed by biological work performed in the Mitochondrial Biology Unit in Cambridge. The strategy of targeting compounds to mitochondria by linking bioactive groups to a lipophilic triphenylphosphonium (TPP) cation is known and was applied in novel ways in this work (Chapters 6-9). TPP-viologen conjugates related to the herbicide, paraquat, were synthesized and one of these, MitoPQ, efficiently generates superoxide selectively in mitochondria. Other probes were prepared for assessing the redox states of mitochondrial thiols and for generating mitochondrial protein perthiols. Preliminary work is presented on strategies for delivering molecular cargoes to mitochondria, so that the cargo is retained in the mitochondrial matrix. Chapter 10 is a summary and suggestions for future work and this is followed by a complete chemistry experimental and materials and methods for biological experiments (Chapter 11) and references