Context effects on the reactivity of 8-oxoguanosine and formation of guanosine-naphthol adducts

Each human cell is comprised of 23 chromosomal pairs that are exceedingly complex in their structure. At the heart of this complexity resides four canonical DNA bases that faithfully base pair in a well defined order. These DNA bases are prone to transformation by biochemical and chemical means, where oxidation reactions can be detrimental to base pairing fidelity. 2'-Deoxyguanosine (dG) bases are the most susceptible to oxidation, yielding the two-electron oxidation product 2'-deoxy-8-oxoguanosine (dOG), providing a promutagenic site within the genome. dOG is unique, since it can hydrogen bond with 2'-deoxycytidine (dC) through its Watson-Crick face, and with 2'-deoxyadenosine (dA) through its Hoogsteen face. Upon replication or transcription through dOG, incorporation of dC or dA can occur, in which the newly formed dOG·dA base pair can lead to a G→T transversion mutation if not properly repaired. dOG is also a hotspot for a second two-electron oxidation, yielding the hydantoin products guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp). Experiments were conducted to observe the effect that base pairing between dOG and dA or dC has on the two-electron oxidation of dOG. The dOG·dC base pair upon oxidation yields Gh, whereas the dOG·dA base pair yields both Gh and Sp. It is proposed that these product differences have their origins in the base pairing effect on the proton transfer pathways during oxidation. The relative reactivity of dOG is also affected by base pairing, where the dOG·dA base pair is more reactive with diffusible oxidants than the dOG·dC base pair. Oxidation of dOG when base paired to dA cannot be repaired to the original dG·dC base pair, locking in the point mutation.;Oxidation of dOG in the presence of nucleophiles other than water provides new products with unique chemical structures, in which 2-naphthol provides two very different products than previously observed. In these studies 2-naphthol was allowed to react with dOG through the course of an oxidation reaction, yielding two unique constitutional isomer products. The structures of these oxidation products can be explained by the redox chemistry of 2-naphthol and its ambidentate nature. These two products were identified by their unique spectroscopic signatures in the NMR and fragmentation masses.