Synthesis of Methylene Blue Analogues as Multifunctional Radical Quenchers, Synthesis of Unnatural Amino Acids and Their Ribosomal Incorporation into Proteins.

摘要

The energy required in a eukaryotic cell is provided by mitochondria. Mitochondrial electron transport chain (ETC) coupled with oxidative phosphorylation generates ATP. During electron transport, electron leakage from the ETC produces reactive oxygen species (ROS). In healthy cells, there are preventive and defense mechanisms in place to manage ROS. Maintaining a steady balance of ROS is very important because overproduction of ROS can lead to several pathological conditions. There are several strategies to prevent ROS production. Addition of external antioxidants is widely used among them. Discussed in the first part of Chapter 1 is the mitochondrial ETC, ROS production and antioxidant strategies.;The second part of Chapter 1 is concerned with ribosomal protein synthesis in bacteria. Ribosome, the organelle that synthesizes proteins with exceptional fidelity, has a strong bias for alpha-L-amino acids. It has been demonstrated that reengineering of the peptidyltransferase center (PTC) of the ribosome could enable the incorporation of both alpha-D-amino acids and beta-amino acids into full length protein.;Oxidative stress is a common cause of various neurological disorders such as Alzheimer's disease and Parkinson's disease. Antioxidative strategies are used widely for the treatment of these disorders. Although several antioxidants demonstrated positive results in vitro as well as in in vivo models, none of them have been effective in clinical settings. Hence, there is an ongoing search for effective neuroprotective drugs. Described in Chapter 2 is the synthesis and biological evaluation of several methylene blue analogues as potentially effective antioxidants for the treatment of pathologies related to oxidative stress.;In Chapter 3, the synthesis and ribosomal incorporation of several rationally designed dipeptidomimetic analogues are discussed. The dipeptidomimetic analogues are structurally similar to the GFP chromophore and, therefore, highly fluorescent. In addition, the backbone of the dipeptidomimetic analogues resemble the peptide backbone of a dipeptide, due to which they can be incorporated into protein by modified ribosomes selected for the incorporation of dipeptides.;Discussed in Chapter 4 is the synthesis of the pdCpA derivatives of several beta-amino acids. The pdCpA derivatives were ligated to tRNA-COH and were used as probes for studying the regio- and stereoselectivity of modified ribosomes.