Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives
Document Type
Article
Publication Date
2-1-2021
Abstract
MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.
Keywords
Oxidized nucleotide, MTH1, Dihalogenated nucleoside derivative, Nucleotide analog
Divisions
pharmacy
Funders
Fukuoka Foundation for Sound Health Cancer Research Fund (JP19H03351)
Publication Title
International Journal of Molecular Sciences
Volume
22
Issue
3
Publisher
MDPI
Publisher Location
ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND