Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives
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...
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my.um.eprints.278462022-04-01T02:37:46Z http://eprints.um.edu.my/27846/ Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives Shi, Hui Ishikawa, Ren Heh, Choon Han Sasaki, Shigeki Taniguchi, Yosuke QD Chemistry 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. MDPI 2021-02 Article PeerReviewed 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 https://doi.org/10.3390/ijms22031274 <https://doi.org/10.3390/ijms22031274>. 10.3390/ijms22031274 |
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QD Chemistry Shi, Hui Ishikawa, Ren Heh, Choon Han Sasaki, Shigeki Taniguchi, Yosuke Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
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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. |
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Article |
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Shi, Hui Ishikawa, Ren Heh, Choon Han Sasaki, Shigeki Taniguchi, Yosuke |
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Shi, Hui Ishikawa, Ren Heh, Choon Han Sasaki, Shigeki Taniguchi, Yosuke |
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Shi, Hui |
title |
Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
title_short |
Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
title_full |
Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
title_fullStr |
Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
title_full_unstemmed |
Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-Deaza-dG derivatives |
title_sort |
development of mth1-binding nucleotide analogs based on 7,8-dihalogenated 7-deaza-dg derivatives |
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MDPI |
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2021 |
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http://eprints.um.edu.my/27846/ |
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