Research Papers:

Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

Ya Gao, Lihan Zhu, Jing Guo, Ting Yuan, Liqing Wang, Hua Li _ and Lixia Chen

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Oncotarget. 2017; 8:95865-95879. https://doi.org/10.18632/oncotarget.21430

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Ya Gao2,*, Lihan Zhu1,*, Jing Guo2, Ting Yuan1, Liqing Wang1, Hua Li1,2 and Lixia Chen1

1Wuya College of Innovation, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People’s Republic of China

2Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China

*These authors have contributed equally to this work

Correspondence to:

Hua Li, email: li_hua@hust.edu.cn

Lixia Chen, email: syzyclx@163.com

Keywords: MTH1; natural inhibitors; farnesyl phenolic compounds; anti-tumor; Ganoderma sinense

Received: May 09, 2017     Accepted: August 17, 2017     Published: September 30, 2017


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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