Electron interaction with modified nucleobases

Radiotherapy faces the problem of lack of oxygen in solid tumors. This hypoxia leads to reduced efficiency of the therapy. Therefore, so-called radiosensitizer molecules are used, which should accumulate in tumor cells and increase the cell sensitivity towards ionizing radiation. One class of radiosensitizers are chemically modified nucleobases, which are integrated into the DNA during its replication and repair. When the ionizing radiation used in radiotherapy interacts with the biological matter, low-energy electrons are released. If a released electron attaches to the incorporated modified nucleobase, it may lead to the irreversible dissociation of this compound. This process is called dissociative electron attachment that produces a reactive radical which may ultimately lead to a severe damage of DNA. In this project, we will study the electron attachment process to modified nucleobases and their possible subsequent dissociation in a combined experimental/computational approach. Experimentally, we will generate an electron beam and collide it with modified nucleobases at well- defined conditions. When an electron attaches to a modified nucleobase, the molecule becomes negatively charged. This negative ion as well as negatively charged dissociation products (if the attachment event leads to dissociation) will be detected by mass spectrometry. By this experimental technique we gain knowledge about the efficiency of the capture process and about possible dissociation pathways. Since these pathways may differ, if the molecule is isolated or solvated, we will also study the electron attachment process, when the modified nucleobase is surrounded by water molecules. The quantum chemical calculations carried out in this project will be used to predict the overall tendency of dissociation for different modifications. Based on that we will synthesize promising modified nucleobases and probe them in the experiment. The calculations will further provide in-depth knowledge on the experimentally observed reaction channels. The results of this project will lead to new knowledge about the processes triggered by an excess electron in biologically important molecules. Moreover, the influence of solvation on the dissociative electron attachment process will be elucidated in the undertaken efforts. The gained knowledge should allow to rationally design molecules prone to low-energy electrons. In the future, such molecules may then be examined with cellular, animal, as well as clinical studies and ultimately applied in radiotherapy as working radiosensitizers.