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. 2024 Dec 26;88(1):80–85. doi: 10.1021/acs.jnatprod.4c01018

Uncovering Hericenones from the Fruiting Bodies of Hericium erinaceus through Interdisciplinary Collaboration

Junhong Wang †, Jing Wu ‡,§, Ryo Yamaguchi ∥, Kaoru Nagai ⊥, Chengwei Liu #, Jae-Hoon Choi †,‡,∇, Hirofumi Hirai †,‡,∇, Xiaonan Xie ○,*, Shoji Kobayashi ∥,*, Hirokazu Kawagishi ‡,§,*
PMCID: PMC11773572  PMID: 39723452

Abstract

graphic file with name np4c01018_0006.jpg

Hericium erinaceus is an edible and medicinal mushroom. Previously, we found hericenones C–H from the fruiting bodies and erinacines A–I from the mycelia of the fungus. These compounds stimulated nerve growth factor (NGF) synthesis both in vitro and in vivo; some have been suggested to be effective in the prevention and treatment of dementia. Recently, the total synthesis of hericenones C–H and their derivatives (1–4) was reported by one of the authors. We considered that the chemical synthetic route would also be reasonable as a biosynthetic pathway of the compounds. Based on the hypothesis, we investigated the endogenous existence of synthetic intermediates and products of the chemical synthesis in the fruiting bodies. The n-hexane-soluble part of the fruiting bodies of H. erinaceus was fractionated, and all the fractions were subjected to a product ion scan and multiple reaction monitoring (MRM) analysis by LC-MS/MS and compared to the authentic synthesized compounds. The analysis indicated the endogenous existence of 1–4 and the dehydrated form of 2 or 3. The dehydrated form was elucidated to be (Z)-5 by chemical synthesis, and a plausible biosynthetic pathway was proposed.

Hericium erinaceus is found in temperate latitudes, such as Asia, Europe, North America, and Oceania. Due to the unique shape of the fruiting body, H. erinaceus is known as Yamabushitake (“mountain monk mushroom”) in Japanese, hóu tóu gu̅ (“monkey head mushroom”) in Chinese, and lion’s mane mushroom in English. H. erinaceus grows on old or dead trunks of broadleaf trees, and the fruiting bodies are not only nutritious but also offer substantial health benefits. In Chinese medical systems, it has been used to promote digestive function and also has been used as an anticancer drug.1 More than 200 secondary metabolites have been isolated and identified from H. erinaceus, including terpenoids, phenolics, steroids, pyrones, fatty acids, and alkaloids.2−4 We reported various resorcinols with enone groups from the fruiting bodies and named them hericenones A to I.5−8 We also reported a series of diterpenoid derivatives (erinacines A to K) isolated from the mycelia.2,9−12 Hericenones C–H and erinacines A–I stimulated biosynthesis of nerve growth factor (NGF) both in vitro and in vivo.5−7,9−11,13 These compounds were the first NGF inducers discovered from nature. NGF is an important protein for supporting the growth and maintenance of peripheral sympathetic neurons, and their essential contribution for the survival and differentiation in neuronal cells has been explored.14,15 Numerous studies have shown that NGF helps the survival and regeneration of neurons during aging and in age-related diseases such as Alzheimer’s disease (AD).16 Clinical trials using the fruiting bodies and/or mycelia of the fungus demonstrated that some symptoms of dementia patients were improved.17−21

In addition to the deficiency of NGF mentioned above, endoplasmic reticulum (ER) stress caused by amyloid-β peptide is known to be one of the etiological factors of AD. ER is a membranous network that provides a unique environment for protein synthesis, folding, and modification.22 ER stress results in apoptosis of neural cells in the brain.23 The group of one of the authors (H.K.) isolated a compound with neuroprotective activity against ER stress from the fruiting bodies of the fungus and determined the structure as 3-hydroxyhericenone F (3-epi-3) (Figure 1).8 In 2021, the group of one of the authors (S.K.) completed the total synthesis of hericenones C to H and some derivatives including (±)-3.24 The NMR data of the synthetic compound (±)-3 were not like those of the reported anti-ER stress compound; instead, the substituted 2,3-dihydrobenzofuran shown as (±)-2 (named hericenone Z) was found to be identical to the previously isolated anti-ER stress compound. Then, H.K. considered that the chemical synthetic route established by S.K. was also reasonable as a biosynthetic pathway of the compounds and hypothesized that the epoxy intermediate 1, the chromane 3, and other analogues (4–6) arising from paths A–C would also be endogenous in the fruiting bodies (Figure 1). Here, we show interdisciplinary collaboration involved in isolation and structure determination, chemical synthesis, instrumental analysis especially mass spectrometry, and biology, which culminated in the proof of the endogenous existence of predicted new compounds.

Figure 1.

Figure 1

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Proposed biosynthetic pathway of new hericenones (1 to 5) based on a chemical synthetic route.

Results and Discussion

Compounds 1–4 were synthesized according to the literature (Figure 1).24 To verify that compounds 1–4 in the hypothesized biosynthetic pathway exist endogenously in the mushroom, the fractions of H. erinaceus extracts were analyzed by means of LC-MS/MS using the synthetic compounds as standards (Scheme S1). Analysis of the standard samples revealed that the retention times of compounds 1 and 2 were at 7.2 min, 3 at 6.5 min, and 4 at 5.5 min (Figure 2). The collision energy was optimized, and the MS/MS transitions selected for the determination of compounds 1–4 were as follows: precursor ions at 587 and 569 and product ions at 177, 331, 331, and 287, respectively, as summarized in Figure 2 and Figure S1.

Figure 2.

Figure 2

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Identification of compounds 1–5 and fractions (upper: synthetic compound; lower: purified fraction) by LC-MS/MS MRM analysis. MRM chromatograms (m/z) in the positive mode of 1 (blue, 587.2/177.1; red, 587.2/331.1; green, 587.2/313.1), 2 (red, 587.2/331.1; blue, 587.2/177.1; green 587.2/569.3), 3 (red, 587.2/331.1; blue, 587.2/179.1; green 587.2/569.3), 4 (blue, 569.4/287.0; red, 569.4/163.1), and 5 (569.3/287.0) are shown.

Then each fraction obtained from the n-hexane-soluble part of the extracts of the fruiting bodies of H. erinaceus was analyzed by LC-MS/MS. The presence of 1–4 was detected in different fractions as shown in Scheme S1. We also detected 1–5 from the crude extracts of H. erinaceus extracted with 1-butanol by LC-MS/MS. The result indicated that these compounds were endogenous in the fruiting bodies and not artifacts generated in the process of fractionation.

During the analysis of the fractions by LC-MS/MS, an ion peak with the same molecular weight as 4 (m/z 569) was detected; however, the retention time was different from that of 4. We considered that the compound that gave the ion peak would be a dehydrated form of 2 or 3, and the synthesis of them was carried out from (±)-2 and (±)-3 (Schemes 1 and 2). For dehydration of (±)-2, the methods via mesylate and triflate were unsuccessful, but a chlorination with thionyl chloride and pyridine followed by β-elimination with DBU gave the desired dehydrated products (±)-5 as an E,Z-mixture.

Scheme 1. Dehydration of (±)-2.

Scheme 1

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Scheme 2. A Plausible Mechanism for the Formation of (±)-5 from (±)-3.

Scheme 2

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Subsequently, we focused on the synthesis of (±)-6, which is the dehydrated form of (±)-3. Mesylation of (±)-3 proceeded quickly to give mesylate (±)-7; however, treatment of (±)-7 with DBU unexpectedly yielded (±)-5 in high yield that was identical to the dehydrated form of (±)-2, and the expected six-membered-ring dehydrated form (±)-6 was not formed at all (Scheme 2). It can be considered that the retro-oxy-Michael reaction of mesylate (±)-7 took precedence over β-elimination, and the resulting phenoxide 8 underwent an intramolecular nucleophilic substitution reaction to form a five-membered ring. The several control experiments suggest that this unexpected ring contraction is due to the presence of ketone, and β-elimination can occur under certain dehydration conditions in the absence of C-3′-ketone (Scheme S2). Based on these chemical reactivities for (±)-2 and (±)-3, it was considered that (±)-5 would be more likely to be endogenous in the mushroom than (±)-6.

The structures of (±)-(E)-5 and (±)-(Z)-5 were determined by interpretation of NMR spectra including DEPT, COSY, HSQC, HMBC, and NOESY (Figures S4–S15). The molecular formulas of (±)-(E)-5 and (±)-(Z)-5 were determined as C35H52O6 by HRESIMS. The observed NOESY correlations and significant downfield chemical shifts for H-7′ (δH 2.03) in E-5 and for H-2 (δH 6.59) and H-3 (δH 3.84, 2.76) in Z-5 caused by deshielding effects by the C-3′-carbonyl group supported the olefin geometries as shown (Scheme 2). The semi-coplanar arrangement of the C-3′-carbonyl group and the C-2–H in the minimum energy conformation of (Z)-5 suggested significant downfield shift of H-2. The observation is consistent with computational predictions using Spartan (Table S1). Each isomer was stable in deuterated benzene, however, rapidly isomerized to a mixture in deuterated chloroform. As shown in Scheme 3, isomerization probably occurred via the enol form. In our analysis, the presence of (Z)-5 was detected in some fractions by LC-MS/MS (Scheme S1), which indicated the endogenous existence of (Z)-5 in the fruiting bodies (Figure 2 and Figure S2).

Scheme 3. A Plausible Mechanism for Isomerization of (±)-5 in CDCl3.

Scheme 3

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(±)-(E)-5 and (±)-(Z)-5 were subjected to a protection assay against ER stress-dependent cell death. The ER stress was induced by addition of tunicamycin (TM) or thapsigargin (TG) into the culture medium of the murine neuroblastoma cell line (Neuro2a) in the presence or in the absence of these compounds.25 TM induces ER stress by inhibiting the synthesis of N-glycoside-linked sugar chains. TG is an inhibitor of Ca2+ ATPase in the ER, and by depleting Ca2+ in the ER, it disturbs intracellular calcium homeostasis and induces ER stress.26 Results indicated that neither (±)-(E)-5 nor (±)-(Z)-5 exhibited significant protective activity against TG toxicity or TM toxicity (Figure S17). (±)-2 and 4 showed significant protective effect against TG-induced neuronal cell death at more than 10 μM.24 A comparison of the structure of 2 and its dehydrated forms, (E)-5 and (Z)-5, indicated the hydroxy group at C-1′ in the side chain of 2 is necessary for the suppression of TG toxicity. (±)-1 was also tested, and no protective activity against TG toxicity or TM toxicity has been found.

Natural products chemistry has mainly focused on discovering small bioactive compounds from nature and proposing their biosynthetic pathways. Then chemical synthesis of natural products is performed sometimes by mimicking the proposed biosynthetic pathway, which is called “biomimetic synthesis”. This study is conceptually opposite; we first estimated the biosynthetic pathway of known hericenones derived from H. erinaceus, based on both the relationship of their structures and the chemical reactivities revealed from synthetic studies. Then a series of synthetic products including the intermediate (1), byproduct (4), and more advanced metabolic product (5) have been proven to be endogenous in the fungus, by cooperation of synthesis and analysis. Our approach enables the discovery of new compounds that are difficult to find from natural sources due to very small quantities or cumbersome structures. This strategy may pave the way for similar studies.

Experimental Section

General Experimental Procedures

1H NMR spectra (one- and two-dimensional) were recorded on a JNM-ECZ400S spectrometer at 400 MHz, and 13C NMR spectra were recorded on the same instrument at 101 MHz (JEOL, Tokyo, Japan). HPLC separations were performed with a Jasco Chromatography Data Station ChromNAV system using reverse-phase HPLC columns (AQ-C18, InertSustain, Tokyo, Japan; ADME, Shiseido, Osaka, Japan). Silica gel plates (Merck F254), ODS gel plates (Merck F254), and silica gel 60 N (Kanto Chemical, Tokyo, Japan) were used for analytical TLC and for flash column chromatography. All solvents used in the isolation experiments were obtained from Kanto Chemical Co. (Tokyo, Japan). Dehydration reactions were performed under an atmosphere of argon. Commercially available dry solvent was used for CH2Cl2. ClCH2CH2Cl was dried over 4 Å molecular sieves before use. Pyridine was distilled from CaH2 and dried over 4 Å molecular sieves before use. Other chemicals were used as received.

Fungal Materials

The fruiting bodies of H. erinaceus were bought from Shinshu kinoko koubou Co., Ltd., Nagano Prefecture, Japan.

Preparation of Semipurified Crude Extracts

The fresh fruiting bodies of H. erinaceus (9.15 kg) was extracted with EtOH (27 L, 3 times) and then with acetone (15 L, 3 times). The solutions were combined, concentrated under reduced pressure, and partitioned between n-hexane and water and ethyl acetate (EtOAc) and water, and the water part was dried up under reduced pressure and then extracted with EtOH, successively. The n-hexane-soluble part (55.9 g) was fractionated by silica gel flash column chromatography (silica gel 60N, CH2Cl2; CH2Cl2:acetone = 90:10, 70:30; CH2Cl2:MeOH = 90:10, 70:30, 50:50; MeOH, 1 L each) to obtain 15 fractions (fractions 1 to 15), and fraction 5 (14.6 g) was further separated by ODS gel flash column chromatography (MeOH:H2O = 99:1) to obtain 18 fractions (fractions 5-1 to 5-18). Fraction 5-6 (1.1 g) was further separated by MPLC (silica gel 60 Å, n-hexane:EtOAc = 70:30, 50:50) to obtain fractions 5-6-1 to 5-6-8. Fraction 5-6-7 (380 mg) was further separated by reversed-phase HPLC (Capcell Pak ADME column, MeCN:H2O = 95:5) to afford fractions 5-6-7-1 to 5-6-7-26.

Synthesis of (±)-5 from (±)-2

Pyridine (11 μL, 0.14 mmol) and SOCl2 (5 μL, 0.07 mmol) were added to alcohol (±)-2 (3.8 mg, 6.5 μmol) in CH2Cl2 (2 mL) at −40 °C. The reaction mixture was gradually warmed to 0 °C over 3 h and quenched by the addition of saturated aqueous NaHCO3 (3.5 mL). The resulting mixture was extracted with n-hexane/EtOAc (1:1 v/v), and the organic layer was washed with brine (3 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residual yellow oil (4.2 mg) was analyzed by 1H NMR, which indicated the formation of mainly four products, including chlorinated intermediates. After the sample was recovered by evaporation, it was dissolved in ClCH2CH2Cl (2 mL) and treated with DBU (15 μL, 0.10 mmol) at 70 °C for 70 min. The reaction mixture was passed through a short silica gel column (eluent:n-hexane:EtOAc = 4:1, v/v) to remove DBU. The collected filtrate was concentrated to yield a mixture of (±)-(E)-5 and (±)-(Z)-5 (2.7 mg, 4.8 μmol, 73%). The ratio of isomers determined by 1H NMR in CDCl3 was 1.7:1 [calculated yields (±)-(E)-5 (1.7 mg, 3.0 μmol, 46%) and (±)-(Z)-5 (1.0 mg, 1.8 μmol, 27%)].

Synthesis of (±)-5 from (±)-3

Et3N (90 μL, 0.65 mmol) and MsCl (10 μL, 0.13 mmol) were added to a solution of alcohol (±)-3 (12.4 mg, 21.1 μmol) and DMAP (4.4 mg, 0.036 mmol) in CH2Cl2 (6 mL). After 34 min at room temperature, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and extracted with n-hexane/EtOAc (1:2, v/v, 2 × 15 mL). The combined organic layer was washed with brine (4 mL), dried over anhydrous MgSO4, filtered, and concentrated. The residual yellow oil (16.7 mg) was analyzed by 1H NMR, which indicated the formation of mesylate (±)-7. After the sample was recovered by evaporation, it was dissolved in ClCH2CH2Cl (6 mL) and treated with DBU (33 μL, 0.22 mmol) at 50 °C for 1 h. After concentration, the residue was repeatedly purified by flash chromatography on silica gel (eluent:n-hexane:EtOAc = 7:1, v/v) to give a less polar (Z)-isomer (0.9 mg, 1.5 μmol, 7%) as a colorless solid, a polar (E)-isomer (5.0 mg, 8.5 μmol, 40%) as a colorless solid, and a mixture of less polar (Z)- and polar (E)-isomers (3.9 mg, 6.9 μmol, 32%).

(±)-(E)-5

Colorless solid; IR (film on ZnSe) v = 2924, 2855, 1732, 1682, 1634, 1614, 1454, 1287, 1252, 1206, 1126 cm–1; 1H NMR and 13C NMR spectra, see Figures S4–S9; HRESIMS m/z 567.3697 [M – H]− (calcd for C35H51O6, 567.3680).

(±)-(Z)-5

Colorless solid; IR (film on ZnSe) ν = 2920, 2851, 1740, 1676, 1616, 1593, 1456, 1308, 1283, 1200, 1167, 1119 cm–1; 1H NMR and 13C NMR spectra, see Figures S10–S15; HRESIMS m/z 569.3840 [M + H]+ (calcd for C35H53O6, 569.3837).

LC-MS/MS Analysis

Endogenous analyses of compounds 1–4 were performed on a triple quadrupole linear ion trap apparatus (QTRAP 5500; AB Sciex, Japan) with an electrospray ionization source connected to a UHPLC system (NexeraX2; Shimadzu, Japan). The UHPLC conditions were as follows: column: InertSustain AQ-C18 (1.9 μM, 2.1 × 150 mm, GL Sciences), solvent: pump A: H2O:MeCN = 40:60, pump B: MeCN:IPA = 10:90), and a gradient of solvent pump B:A = 80:20 was used. After 15 min, the solvent was set to pump B:A = 10:90. The flow rate was 0.2 mL/min, the column oven temperature was 30 °C, and the injection volume was 2 μL. Isocratic UPLC was performed to separate stereoisomers of 5 (column, CHIRAL-PACK AD-3C, 150 × 2.1 mm, 3.0 μm, CPI Company, Japan; 60% MeCN/2-propanol; flow rate, 0.2 mL/min, 5 °C). (±)-(E)-5 and (±)-(Z)-5 appeared as independent peaks, respectively, but optical resolution of both (±)-(E)-5 and (±)-(Z)-5 was not achieved. MS/MS spectra were recorded as product ions (m/z 40–950) in positive ion mode by linear ion trap (LIT). The measurement conditions were set as follows: ion source: 400 °C; curtain gas: 20 psi; collision activation dissociation (CAD) gas: 7 psi; ion source gas: 80 psi; ion source gas 2:70 psi; and ion spray voltage in positive ion mode: 5500 V. All gases were nitrogen. The declustering, entrainment, and collision cell exit potentials were maintained at 60, 10, and 15 V, respectively. Multiple reaction monitoring (MRM) was used for identification of 1–5 in extracts by comparing retention times with synthetic standards. Chromatograms and mass spectra were analyzed by using ABSciex Analyst software.

Neuroprotective Assay

Materials for Neuroprotective Assay

Neuro2a cells were obtained from the Health Science Research Resources Bank, Japan, and maintained in Dulbecco’s modified Eagle’s medium (D-MEM) (Sigma, USA) supplemented with 10% fetal bovine serum (FBS) at 37 °C in a humidified atmosphere containing 5% CO2 in air, unless particularly noted. Tunicamycin and thapsigargin were obtained from Nacalai Tesque and Sigma, respectively, and were dissolved in D-MEM without FBS at concentrations of 5.0 μg/mL for TM and 100 nM for TG. The test samples were first completely dissolved in DMSO (100 mM) and then diluted with D-MEM without FBS to 10–100 μg/mL. Visually, no precipitation was detected at this point.

Cell Protection Assay

Neuro2a cells were cultured in D-MEM with FBS (70 μL) for 22–24 h in 96-well plates, starting at a cell density of 2000, 3000, or 5000 cells/well. The medium was removed, and immediately the cells were pretreated with varying concentrations (10–100 μg/mL) of test compounds in D-MEM without FBS (70 μL) for 2 h. Next, the ER stressors were added to the medium (final concentration: 0.5 μg/mL for TM and 10 nM for TG), and the cells were incubated for an additional 22 h. After this treatment, cell viability was measured by using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay as described previously. Briefly, the medium was replaced with 0.25 mg/mL of MTT in D-MEM without FBS (70 μL), and the cells were incubated for 2 h. Incubation was terminated by the addition of 15% sodium dodecyl sulfate (w/v) and 50% N,N-dimethylformamide (v/v) in water (70 μL). The absorbance of the reaction mixture at 570 nm was measured with a microplate reader.

Statistical Analysis

Data collected were analyzed statistically using Tukey–Kramer multiple comparison tests to determine significant differences in the data among the groups. p values less than 0.01 or 0.05 were considered significant. The values are expressed as the means ± SD.

Acknowledgments

This work was supported by the Specific Research Grant from Takeda Science Foundation to H.K. and JSPS KAKENHI (JP21K05407 and JP24K08737) to S.K. We thank M. Kubo (Shinshu Kinoko Koubou Co., Ltd., Nagano Prefecture, Japan) for providing the mushrooms.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c01018.

  • Additional information (PDF)

  • Raw NMR data (ZIP)

The authors declare no competing financial interest.

Supplementary Material

np4c01018_si_001.pdf (5.6MB, pdf)
np4c01018_si_002.zip (57.9MB, zip)

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Associated Data

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Supplementary Materials

np4c01018_si_001.pdf (5.6MB, pdf)
np4c01018_si_002.zip (57.9MB, zip)

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