Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense

Abstract

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.

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

“…Gao et al. 24 isolated eight farnesyl phenolic (FP) compounds with a coumaroyl moiety, FP-1 to 8, from the fruiting bodies of Ganoderma sinense , and these compounds subsequently proved to actively inhibit MTH1 with the IC 50 values ranging from 8.6 to 28.5 μmol/L ( Fig. 4 ).…”

Triterpenoids from Ganoderma lucidum and Their Potential Anti-inflammatory Effects

“…G. lucidum and its closely related species G. sinense are suggested be used interchangeably as Lingzhi according to Chinese Pharmacopoeia. ,,, Chemical investigations on the two species of Ganoderma based on multiple analytic technologies or chemical separation have been carried out, and triterpenoids and polysaccharides were determined as the major constituents ,− of G. lucidum , while studies on G. sinense are relatively few, showing the presence of meroterpenoids, steroids, alkaloids, triterpenoids, and polysaccharides. ,− Comparing the chemical constituents from two official species of Ganoderma genus demonstrated the significant difference on type and content of triterpenoids by high performance liquid chromatography coupled with photodiode array (HPLC-PDA) and high performance liquid chromatography–mass spectrometry (LC–MS) analyses, with about 10 times higher in G. lucidum than G. sinense , and lack of common triterpenes in G. sinense . , While the similar chemical features of polysaccharides between both species were observed, , they also showed similar antitumor and immunomodulating activities . Although polysaccharides as the active principles could explain to some extent the official use of both species as Lingzhi, the influence of numerous small-molecular constituents and their different bioactivities in both species remains to be further investigated and provides a deeper explanation for their exchangeable usage in China.…”

Caragana rosea Turcz Methanol Extract Inhibits Lipopolysaccharide-Induced Inflammatory Responses by Suppressing the TLR4/NF-κB/IRF3 Signaling Pathways

“…It can induce the production of inflammatory mediators such as chemokines and cytokines. Many natural herb derived extracts used in Chinese traditional medicine have been reported as anti-inflammatory drugs that can be used to treat diseases such as colitis and gastritis [22,23]. Cr-ME is derived from a small shrub with anti-inflammatory properties found in Northern and Eastern China, and it has proven to be effective in treating models of fever, asthma, and cough [16,18].…”

“…In addition, we also performed the CETSA to determine whether Cr-ME interacts directly with Src in vitro and to verify the interaction between the target protein and test compound through ligand-mediated stabilization of proteins [22,23]. In the CETSA, cells with and without the test compound are damaged thermally to see whether binding between the compound and the target produces thermostabilization of the target [24].…”

“…RAW264.7 cells were seeded and incubated overnight, followed by pre-treatment with Cr-ME (100 µg/mL) for 30 min and treatment with LPS (1 µg/mL) for 5, 15, 30, and 60 min. The cells were harvested at those time points, and whole-cell protein lysates were prepared as previously described [22]. Nuclear lysates were prepared in a three-step procedure as reported previously [67].…”