Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives

Shi, Hui and Ishikawa, Ren and Heh, Choon Han and Sasaki, Shigeki and Taniguchi, Yosuke (2021) Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives. International Journal of Molecular Sciences, 22 (3). ISSN 1422-0067, DOI

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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.

Item Type: Article
Funders: Fukuoka Foundation for Sound Health Cancer Research Fund (JP19H03351)
Uncontrolled Keywords: Oxidized nucleotide; MTH1; Dihalogenated nucleoside derivative; Nucleotide analog
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Pharmacy
Depositing User: Ms Zaharah Ramly
Date Deposited: 01 Apr 2022 02:37
Last Modified: 01 Apr 2022 02:37

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