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Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707067/ https://www.ncbi.nlm.nih.gov/pubmed/29221173 http://dx.doi.org/10.18632/oncotarget.21430 |
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author | Gao, Ya Zhu, Lihan Guo, Jing Yuan, Ting Wang, Liqing Li, Hua Chen, Lixia |
author_facet | Gao, Ya Zhu, Lihan Guo, Jing Yuan, Ting Wang, Liqing Li, Hua Chen, Lixia |
author_sort | Gao, Ya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5707067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57070672017-12-07 Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense Gao, Ya Zhu, Lihan Guo, Jing Yuan, Ting Wang, Liqing Li, Hua Chen, Lixia Oncotarget Research Paper 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. Impact Journals LLC 2017-09-30 /pmc/articles/PMC5707067/ /pubmed/29221173 http://dx.doi.org/10.18632/oncotarget.21430 Text en Copyright: © 2017 Gao et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Gao, Ya Zhu, Lihan Guo, Jing Yuan, Ting Wang, Liqing Li, Hua Chen, Lixia Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title | Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title_full | Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title_fullStr | Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title_full_unstemmed | Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title_short | Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense |
title_sort | farnesyl phenolic enantiomers as natural mth1 inhibitors from ganoderma sinense |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707067/ https://www.ncbi.nlm.nih.gov/pubmed/29221173 http://dx.doi.org/10.18632/oncotarget.21430 |
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