Inhibitory Effect of 8‐Halogenated 7‐Deaza‐2′‐deoxyguanosine Triphosphates on Human 8‐Oxo‐2′‐deoxyguanosine Triphosphatase, hMTH1, Activities

Yin, Yizhen; Sasaki, Shigeki; Taniguchi, Yoshihiro

doi:10.1002/cbic.201500589

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…Therefore, MTH1 may be only associated with tumor cell growth, which represents a new attractive therapeutic targets for the treatment of cancers these days [ 8 ]. Although there are a few chemically synthesized small molecule MTH1 inhibitors available in recent years, such as TH287/TH588, ( S )-crizotinib, SCH51344, organometallic complexes and 8-halogenated 7-deaza-2′-deoxyguanosine triphosphates [ 2 , 8 , 9 , 10 ]. Nevertheless, there are no any natural MTH1 inhibitors so far and the MTH1 inhibitors mentioned above are far more from clinical use.…”

Section: Introductionmentioning

confidence: 99%

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

et al. 2017

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Cancer cells are more addictive to MTH1 than normal cells because of their dysfunctional redox regulations. MTH1 plays an important role to maintain tumor cell survival, while it is not indispensable for the growth of normal cells. Farnesyl phenols having a coumaroyl substitution are rather uncommon in nature. Eight farnesyl phenolic compounds with such substituent moiety (1–8), including six new ones, ganosinensols E–J (1–6) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense. Four pairs of enantiomers 1/2, 3/4, 5/6 and 7/8 were resolved by HPLC using a Daicel Chiralpak IE column. Their structures were elucidated from extensive spectroscopic analyses and comparison with literature data. The absolute configurations of C-1′ in 1–6 were assigned by ECD spectra. These compounds were predicted to have high binding affinity to MTH1 through virtual ligand screening. The enzyme inhibition experiments and cell-based assays confirmed their inhibitory effects on MTH1. Furthermore, siRNA knockdown experiments and the cellular thermal shift assay (CETSA) confirmed that the farnesyl phenolic enantiomers specifically bound with MTH1 in intact cells. Meanwhile, the low cytotoxicity of 1–8 on normal human cells further verified their good selectivity and specificity to MTH1. These active structures are expected to be potential anti-cancer lead compounds.

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Section: Introductionmentioning

confidence: 99%

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

et al. 2017

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“…Since the influence of the size of the halogen atom was small, these effects were attributed more to the electronic change of the nucleobase position, i.e., stacking interaction, than to the direct interaction of the halogen atom with the enzyme. Compared with the IC 50 value of TH287 (Table 1, Entry 13) [28], which is the strongest class inhibitor as a small molecule, the IC 50 value of our triphosphate compounds were about 10-fold different. These results were also shown to be very interesting as an inhibitory effect on MTH1 activity.…”

Section: Inhibitory Effects Of New 7-deaza-dg Derivatives On the Hydrmentioning

confidence: 72%

“…To address this discrepancy and reveal its functions or properties in living cells, we developed 8-halogenated 7-deaza-dGTP, an 8-oxo-dGTP analogue [27][28][29], and γ-N-modified 8-oxo-dGTP [30] as a MTH1-binding compound. This structural mimicry of a natural product is important for elucidating the functions or mechanisms of intracellular events.…”

Section: Introductionmentioning

confidence: 99%

“…for C 13 H 14 N 4 O 5 Cl 2 Na [M + Na] + : 582.8946, found: 582.8971.3.1.3. General Procedure for the Synthesis of 5 -Monophosphate CompoundsThe corresponding 3 -OAc compounds(14,15,16, and 17[28]) (0.021 mmol) and 2-cyanoethylphosphate (0.11 mmol) were dissolved in pyridine (0.58 mL), under an argon atmosphere at room temperature, and DCC (0.15 mmol) were then added to the reaction mixture. The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in 28% ammonia solution and stirred for 6 h at 40 • C. The reaction mixture was filtered off, and the filtrate was washed with diethyl ether, then aqueous layer was concentrated under reduced pressure.…”

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confidence: 99%

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Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives

Shi

Ishikawa

Heh

et al. 2021

IJMS

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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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Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Yin

Chen

2020

Acta Pharmaceutica Sinica B

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Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

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Inhibitory Effect of 8‐Halogenated 7‐Deaza‐2′‐deoxyguanosine Triphosphates on Human 8‐Oxo‐2′‐deoxyguanosine Triphosphatase, hMTH1, Activities

Cited by 8 publications

References 40 publications

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

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