| Reactive oxygen species (ROS), which are generated from various sources, are very deleterious in nature. ROS damage biological components like DNA, RNA, proteins and lipids through liberation of free radicals. A lot of research has focused on DNA damage through oxidation. Studies on RNA oxidation have, however, received much less interest until the past decade. RNA oxidation was identified to play a significant role in the etiology of neurological diseases such as Alzheimer's and Parkinson's. The goal of this project is to develop the tools required for understanding the mechanisms involved in oxidative damage to RNA at a molecular level. An approach was taken which involved the generation of site specific radicals on nucleosides. Two nucleosides, uridine and pseudouridine, which are specifically found in RNA, were considered for this work. This study focuses on the generation of C5'-nucleosidylradicals from photolabile radical precursors and understanding the mechanisms of formation of radical derived products. For this purpose, syntheses were designed for the preparation of both C5'-pivaloyl substituted uridine and pseudouridine. C5'-pivaloyluridine was successfully synthesized and utilized for the generation of the C5'-uridinylradical through Norrish type I photocleavage. Photolyses were carried out under anaerobic and aerobic conditions in the presence and absence of hydrogen atom donors. Product formation was analyzed by HPLC and mass spectrometry. The formation of the reduction product was observed in the presence of a hydrogen atom donor. Along with the reduction product, base elimination was observed under all photolysis conditions. The synthesis of the C5'-pseudouridinylradical precursor is in progress. |
