Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Gao, Ya, Zhu, Lihan, Guo, Jing, Yuan, Ting, Wang, Liqing, Li, Hua, Chen, Lixia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
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
_version_ 1783282348930891776
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
work_keys_str_mv AT gaoya farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT zhulihan farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT guojing farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT yuanting farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT wangliqing farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT lihua farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense
AT chenlixia farnesylphenolicenantiomersasnaturalmth1inhibitorsfromganodermasinense