Structural analysis of 6-thioguanine in duplex DNA by NMR spectroscopy
Document Type Dissertation/Thesis
6-Thioguanine (??G) is an antimetabolite chemotherapy drug approved by the FDA in 1966 and used primarily to treat leukemia. Despite its long history as a therapeutic agent, its biochemical mode of action is still not completely understood. Studies suggest that ??dG is converted to deoxy-6-thioguanosine triphosphate (??dGTP) and incorporated into DNA, leading to death of rapidly dividing cells. It has been shown that ??dG disrupts the structure of self-complimentary duplex DNA, but a high-resolution X-ray or NMR structure of ??dG in duplex DNA is unavailable at this time. In this study, we have synthesized an 11 base pair DNA duplex., d(CGTTAGATGCC}(GGCATCTAAGC), and an identical DNA duplex with one central guanine replaced by ??dG. Using ?H NMR spectroscopy, we have analyzed the structural differences between unmodified and ??dG modified DNA duplexes. Our data suggests that the structure of the ??dG modified DNA duplex does not differ significantly from the structure of the unmodified DNA duplex and that the ??dG-dC base pair resembles a normal Watson-Crick base pair.