Development of Damaged Nucleoside Mimics for Inhibition of Their Repair Enzymes.

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is a representative of nucleoside damage, which is generated by the reaction of the 8 position of dG with reactive oxygen species. Abundant 8-oxo-dG in DNA exhibits genotoxicity and has been linked to aging and disease, such as cancer. As the metabolism of cancer cells is much faster than that of normal cells, the oxidized product of the oligonucleotides and the nucleotide pool produces 8-oxo-dG and 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), respectively. Human oxoguanine glycosylase (hOGG1) shows base excision activity for 8-oxo-dG in duplex DNA. On the other hand, human mutT homologue protein (hMTH1, also known as NUDT1) is important for oxidized nucleotide removal including 8-oxo-dGTP, and it is reported that the presence of hMTH1 is not essential for normal cells but is required for the survival of cancer cells. Therefore, we designed and synthesized 8-halogenated 7-deaza-2'-deoxyguanosine triphosphate (8-halo-7-deaza-dGTP) derivatives as mimics of 8-oxo-dGTP in order to interact with hMTH1. The 8-halo-7-deaza-dGTP derivatives were poor substrates for but strong binders to hMTH1. Interestingly, they exhibited strong competitive inhibition of hMTH1 in the hydrolysis of 8-oxo-dGTP. This inhibitory effect is caused by the slower rate of hydrolysis due to possible small enzyme structural changes. Although the detailed inhibition mechanism of the hydrolysis activity of hMTH1 is unknown, this result is the first to demonstrate the potential of nucleoside triphosphate derivatives as antitumor agents.