Date of Graduation
1996
Document Type
Thesis
Abstract
In biology and medicine, free radicals are now of intense interest because they have been shown to be involved in many different aspects of metabolism, ranging from oxygen consumption and autocatalysis to xenobiotic metabolism. Formation of free radicals in various systems may contribute to diseases and degenerative processes. Free radicals attack guanine in DNA to give 8-substituted guanine derivatives including C-8-oxo-2{dollar}\\sp\\prime{dollar}-deoxyguanosine (oG) and C-8-aryl guanine derivatives via hydroxy and aryl radicals, respectively. The work to be described herein resulted from studies of both adducts in relation to carcinogenesis and other pathogenesis. This dissertation is divided into five chapters. Chapter I investigates a novel route for chemical synthesis of the oG derivative for automated DNA synthesis. These investigations were carried out in order to improve the efficiency and the reaction yield of the oG derivative. The new route is based on a novel synthetic method for the preparation of oG from dG. Chapter II describes an investigation into conformational changes in DNA resulting from oG:G mismatches in DNA. The stability of this mismatch was examined. The effects of the oG:G mismatches on the structure of telomeric DNA is described in Chapter III. Based on the results in Chapter II, an oG:G mismatch is expected to disrupt the normal structure of telomeric DNA and this was found here. This result supports our hypothesis that the genotoxicity of oG may be related to the genomic instability caused by the introduction of an oG into a normal G-quartet structure. C-8-Aryl guanine and its derivatives of four arenediazonium ions have been examined to probe for mechanism of genotoxic potency of arenediazonium ions in Chapter IV. The formation of aryl radicals from arenediazonium ions and the formation of C-8-aryl-guanine adducts were demonstrated. In addition, adduct formation could be correlated with their arenediazonium ion genotoxicity. In our investigations of oG and C-8-aryl-guanine adducts, NMR spectroscopy was heavily relied upon since it is a powerful technique for studying molecular structure and dynamic interaction. In Chapter V, we discuss several NMR techniques and their applications to our problems. This investigation supports further work on NMR applications.
Recommended Citation
Yau, Wai-Ming, "Formation and structure of C-8-oxo/aryl-guanine adducts in DNA." (1996). Graduate Theses, Dissertations, and Problem Reports. 10077.
https://researchrepository.wvu.edu/etd/10077