ABSTRACT
Hericium erinaceus (Bull.) Pers., an edible and medicinal mushroom, has garnered significant scientific interest due to its rich array of bioactive compounds. Extensive research has highlighted the pharmacological properties of its constituents, including neuroprotective, neurotrophic, immunomodulatory, and anticancer activities. Among interesting bioactive secondary metabolites in H. erinaceus, hericenones—a structurally unique class of geranyl‐resorcinol derivatives—have emerged as particularly promising pharmacological agents. This review comprehensively covers the 24 known natural hericenones and one semisynthetic derivative, detailing their structural elucidation with a focus on characteristic NMR spectroscopy to provide a systematic identification guide. Furthermore, the review discusses their biosynthesis, isolation methodologies, and beneficial biological properties. These include the stimulation of nerve growth factor (NGF), as well as anti‐inflammatory, antioxidant, anticancer, antidiabetic, antiplatelet, and anti‐obesity. By integrating chemical and pharmacological perspectives, this work underscores the promise of hericenones as lead compounds for the development of novel therapeutics.
Keywords: anticancer, anti‐inflammatory, anti‐obesity, antiplatelet, mushroom, neurological agents
1. Introduction
Mushrooms have emerged as a significant focus in functional food and nutraceutical research due to their unique biosynthetic ability to produce essential nutrients and therapeutic secondary metabolites. Among the interesting mushrooms, Hericium erinaceus (Bull.) Pers., a medicinal mushroom of the Hericiaceae family, stands out with a long history of use as a food and traditional medicine in East Asia. Commonly known as “Lion's Mane” in English, “Yamabushitake” in Japanese, and “Hóu Tóu Gū” in Chinese, this mushroom is native to temperate regions across Asia, Europe, and North America [1, 2]. In traditional Chinese medicine (TCM), H. erinaceus has been primarily employed to promote digestive function and treat gastric ailments [1, 2]. Modern research has expanded its therapeutic potential to include benefits for neurological disorders, cognitive function, cancer, and diabetes [2, 3, 4].
The pharmacological properties of H. erinaceus are attributed to its unique and diverse chemical profile, with over 200 compounds identified, including steroids, terpenoids, phenolics, and alkaloids [4, 5]. Among the most biologically significant molecules are the low‐molecular‐weight geranyl‐resorcinols, predominantly isolated from the fruiting bodies and known as hericenones, and the diterpenoid erinacines, biosynthesized mainly in the mycelia [3]. These compound classes exhibit a wide range of health promoting properties, including antitumor, antioxidant, antidiabetic, and notably, neuroprotective effects [3].
Hericenones are characterized by a geranyl‐resorcinol core, often featuring a benzaldehyde or chromone moiety, and some possess fatty acid side chains (Figure 1). A key mechanism underlying their neuroprotective potential is the stimulation of nerve growth factor (NGF) biosynthesis and the promotion of neurite outgrowth [2, 6, 7]. These beneficial health effects highlighting hericenones as promising candidates for addressing age‐related neurological disorders such as Alzheimer's and Parkinson's diseases, as NGF plays a crucial role in neuronal survival, differentiation, and synaptic plasticity [8, 9]. The antioxidant and anti‐inflammatory properties of hericenones further contribute to their therapeutic potential [10].
FIGURE 1.
Core structures of hericenones and their fatty acid side chains.
Despite their promising medicinal properties, a comprehensive review dedicated to chemistry, structural elucidation, and identification of hericenones is notably unavailable in the literature. This gap impedes a focused understanding of the structure–activity relationships (SARs) that underpin their bioactivity. To address this, the present work provides a systematic overview of these bioactive metabolites, detailing their structural diversity, biosynthesis, natural occurrence, and characteristic NMR spectroscopic features. By consolidating the current knowledge of their pharmacological significance, this review aims to clarify the critical link between the specific chemical composition of H. erinaceus and its reported health benefits, thereby providing a foundational resource for future research in neuroprotective and anticancer drug discovery.
2. Methodology
In this work, we conducted a comprehensive literature search on hericenones through several databases, including SciFinder, Scopus, and PubMed. A detailed search was performed using the keywords “hericenones” and “Hericium erinaceus secondary metabolites.” The review covers data published from the first report in 1990 up to July 2025. The inclusion criteria encompassed all original research and review articles focusing on the isolation, structural elucidation, biosynthesis, and biological activities of hericenones. Studies not directly relevant to hericenones were excluded.
3. Biosynthesis of Hericenones
The biosynthesis of hericenones in H. erinaceus and related fungal species represents a classic meroterpenoid pathway, merging precursors from the polyketide and mevalonate pathways. The biosynthesis pathway is initiated by the formation of an aromatic polyketide core, orsellinic acid, a common precursor to hericenones, hericerin, and erinacerins, through sequential condensation of acetyl‐CoA and malonyl‐CoA units catalyzed by a type I polyketide synthase (PKS). This benzoic acid derivative then undergoes modification by two enzymatic steps, a prenyltransferase (PT) that mediates the transfer of a geranyl diphosphate (GPP) moiety to the aromatic ring, yielding farnesylated orsellinic acid, while a carboxylic acid reductase (CAR) reduces the carboxyl group to an aldehyde, collectively producing an intermediate, ilicicolin B (farnesylated orsellinic aldehyde). This branched aldehyde, ilicicolin B, undergoes oxidation and cyclization to produce a structurally diverse array of hericenone derivatives. In some hericenone derivatives, a nitrogen substituent in the structures is derived from an amine or amino acid (R′─NH2). An alternative route is proposed to produce specific derivatives, beginning with o‐methylation and benzylic oxidation of o‐orsellinaldehyde, followed by geranylation and condensation with fatty acids [2, 11, 12]. The proposed biosynthetic pathway leading to various hericenone structures is summarized in Figure 2.
FIGURE 2.
Proposed biosynthetic pathway of hericenones. CAR, carboxylic acid reductase; FPP, farnesyl pyrophosphate; GPP, geranyl pyrophosphate; PKS, polyketide synthase; PT, prenyl transferase.
4. Occurrence and Biological Significance of Hericenones
This review comprehensively covers twenty‐five hericenone compounds (1–25) identified from Hericium species to date. Structural features, natural occurrence, and isolation methodology will be detailed in the subsequent subsections. Furthermore, the reported biological activities for each hericenone—spanning neuroprotective, cytotoxic, anti‐inflammatory, and antimicrobial effects—will be presented and discussed, providing a foundational resource for future research on these promising natural products. Hericenone compounds covered in this review were identified as hericenone A (1), hericenone B (2), hericenone C (3), hericenone D (4), hericenone E (5), hericenone F (6), hericenone G (7), hericenone H (8), hericenone Z (9b), hericenone I (10), hericenone J (11), isohericenone J (12), hericenone K (13), 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14), hericenone L (15), isohericenone (16), 4‐[3′,7′–dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methyoxybenzylalcohol (17), deacylhericenone (18), hericenone M (19), hericenone N (20), hericenone O (21), hericenone P (22), hericenone Q (23), hericenone R (24), [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25) as seen in Figure 3.
FIGURE 3.
Structures of compounds (1–25) covered in this review.
4.1. Hericenones With Cytotoxic Activity
H. erinaceus (Lion's Mane mushroom) exhibits significant anticancer properties, demonstrated through its ability to inhibit the growth of several cancer cell lines. The isolated compounds can suppress proliferation, induce cell cycle arrest, and promote apoptosis in cancer cells. Furthermore, they can inhibit metastasis by interfering with key signaling pathways, and the activity is often associated with specific metabolites such as hericenones, hericerins, and erinacines [13, 14].
In 1990, Kawagishi and colleagues conducted the first isolation study of bioactive metabolites from H. erinaceus mushroom (Yamabushitake) [5]. Their work on acetonic extract of the mushroom's fruiting bodies led to the identification of two phenolic hericenones, namely, 6‐[(2′E)‐3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl]‐7‐hydroxy‐5‐methoxyphthalide, commonly known as hericenone A (1) and 6‐[(2′E)‐3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl]‐7‐hydroxy‐5‐methoxy‐N‐(2″‐phenylethyl)‐1‐isoindolinone, known as hericenone B (2). Cytotoxicity assays against HeLa cells revealed that both compounds were active, though hericenone B (2) was markedly more potent, achieving complete inhibition at 6.3 µg/mL compared to 100 µg/mL for hericenone A (1). This enhanced activity was preliminarily attributed to the presence of an N‐substituted γ‐lactam moiety in hericenone B's structure [5].
It is worth mentioning that the structure of hericenone A (1) was revised via chemical synthesis to (E)‐5‐(3,7‐dimethyl‐5‐oxoocta‐2,6‐dien‐1‐yl)‐4‐hydroxy‐6‐methoxyisobenzofuran‐1(3H)‐one (1a) [15], while the structure of hericenone B (2) was corrected to the carbonyl regioisomer (2a) based on the total synthesis of eight compounds [16].
In a study by Ma et al. [1], hericenones C (3), F (6), and I (10) as well as hericenes A and D, were isolated from the chloroform‐soluble fraction of a methanolic extract derived from H. erinaceus fruiting bodies. Notably, the structure of hericenone I (10) as depicted in their article was inconsistent with the original structural characterization by Ueda et al. [17]. Subsequent analysis revealed that the compound described by Ma et al. [1] was instead [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25), which was conclusively isolated and identified in a study conducted by Ruan et al. [18]. Using the MTT assay, these compounds were evaluated for their cytotoxic activity against esophageal cancer cells (EC109 cell lines). At a concentration of 1 × 10−3 mol/L, hericenones C (3), F (6), and [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25) displayed cytotoxicity with growth inhibition percentages of 57.75%, 59.23%, and 65.34%, respectively [1].
A study conducted by Li et al. [19] reported one new aromatic hericenone derivative, namely, isohericenone J (12), together with a known compound, hericenone J (11), purified from the methanolic extract of H. erinaceus fruiting bodies as shown in Figure 3. Using the MTT assay, the antitumor activity of the isolated compounds was evaluated in human acute promyelocytic leukemia HL‐60 cells. Hericenone J (11) and isohericenone J (12) significantly demonstrated cytotoxicity toward HL‐60 cells with IC50 values of 4.13 ± 0.20 and 4.10 ± 0.21 µM, respectively. In addition, both compounds showed cytotoxic effects against normal human lung fibroblast cell lines (HEL‐299) with IC50 values of 5.79 ± 0.60 and 5.07 ± 0.60 µM, respectively [19].
In 2012, chemical investigation of the chloroform‐soluble fraction obtained from the methanolic extract of H. erinaceus fruiting bodies afforded hericenone L (15) and hericenone C (3). Hericenone L (15) demonstrated in vitro cytotoxicity against oesophageal EC109 tumor cells with an IC50 value of 46 µg/L [20].
A new cytotoxic alkaloid, classified as isoindolinone and named isohericenone (16) was isolated from H. erinaceus in 2012 by Kim et al. [21]. The sulforhodamine B (SRB) bioassay guided screening of a methanolic extract of Korean wild mushrooms indicated that H. erinaceus displayed significant cytotoxic activity against A549, SK‐OV‐3, SK‐MEL‐2, and HCT‐15 cell lines. Consequently, the chemical investigation of the methanolic extract led to the isolation of this new isoindolinone alkaloid, namely, isohericenone (16), alongside some known compounds, including hericenone A (1), hericenone D (4), hericenone E (5), hericenone F (6), hericenone J (11), and 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) [21].
Importantly, isohericenone (16) exhibited proliferation inhibitory activity against cancer cell lines, A549 (lung cancer cell line), SK‐OV‐3 (ovarian adenocarcinoma cell line), SK‐MEL‐2 (human melanoma cell line), and HCT‐15 (colon cancer cell line) with IC50 values of 2.6, 3.1, 1.9, and 2.9 µM, respectively. Furthermore, (14) demonstrated antiproliferative activity against A549, SK‐OV‐3, SK‐MEL‐2, and HCT‐15 cell lines with IC50 values 17, 11, 13, 16 µM, respectively. Interestingly, (14) and (16) contribute to the antitumor activity of H. erinaceus with particular importance being that these compounds may be developed as effective anticancer agents [21].
A chemical study by Ashour et al. [14] indicated that the investigation of the aqueous ethanolic (50%) extract obtained from H. erinaceus mushroom with several chromatography procedures led to the isolation of hericenone D (4) and hericenone I (10), as well as other 11 metabolites, including two newly purified isoindolin‐1‐ones, identified as erinacerins M and N, alongside other known compounds. The anticancer activity of hericenone I (10) was evaluated against various cancer cell lines, including human neuroblastoma cells SH‐SY5Y, human astrocytoma cells 1321N1, human colorectal cancer cells, HCT‐116 and Caco‐2, ovarian carcinoma cells OVK18, and human cervical cancer cells HeLa. It displayed activity with IC50 values of 36.69 ± 2.44 µM against SH‐SY5Y, 41.66 ± 3.20 µM against 1321N1, 7.66 ± 0.87 µM against HCT‐116, 49.53 ± 2.00 µM against Caco‐2, 0.99 ± 0.78 µM against OVK18, and 25.94 ± 9.23 µM against HeLa cells.
A similar study published in 2016 by Wang et al. [13] reported the isolation of hericenone A (1) and hericenone J (11) from 70% ethanolic extract of H. erinaceus dried fruiting bodies. The cytotoxicity of compounds (5–20 µg/mL) was evaluated against human liver cancer cells, SMMC‐7221 and MHCC‐97H. In a dose‐dependent manner, hericenone A (1) and hericenone J (11) inhibited the proliferation of liver cancer cells SMMC‐7221. On the other hand, hericenone A (1) inhibited the growth of MHCC‐97H cells. Taking into consideration that hericenone A (1) (20 µg/mL) demonstrated the highest growth inhibition activity toward SMMC‐7221 and MHCC‐97H, it might be used as a lead compound for developing antitumor therapy [13].
In 2019, Chen et al. [22] investigated the pharmacological activity of an ethanolic extract from the New Zealand mushroom Hericium novae‐zealandiae. While the study identified hericenone C (3) among the constituents, the compound itself was not purified. The anti‐proliferative effect of the ethanolic extract (0.35–6.67 mg/mL) and hericenone C (3) (0.38–8.20 µM) was evaluated against three prostate cancer cell lines (DU145, LNCaP, and PC3). The crude ethanolic extract demonstrated potent activity with IC50 values ranging from 0.19 to 0.33 mg/mL, although it also showed cytotoxicity against noncancerous HEK293 cells (IC50 = 0.15 mg/mL). In contrast, hericenone C (3) exhibited weaker activity, with an IC50 value exceeding 8.2 µM. Mechanistic studies using RT‐qPCR suggested that the extract's anti‐proliferative effect mediated through the induction of apoptosis—evidenced by the upregulation of CASP3, CASP8, CASP9, and an increased Bax/Bcl‐2 ratio—and anti‐inflammatory activity, via the downregulation of interleukin‐6 (IL‐6) and upregulation of IL‐24.
In a patent published in 2018 [23], 5‐[(2E)‐3,7‐dimethyl‐5‐carbonyl‐2,6‐octadiene‐1‐yl]‐2,3‐dihydro‐4‐hydroxy‐6‐methoxy‐2‐(2‐hydroxy)isoindole‐1‐one, named hericenone M (19) and 5‐[(2E)‐3,7‐dimethyl‐2,6‐octadiene‐1‐yl]‐2,3‐dihydro‐4‐hydroxy‐6‐methoxy‐2‐(2‐hydroxy)isoindole‐1‐one, named hericenone N (20), have been reported from the 95% ethanolic mycelia extract of H. erinaceus. In this study, the 50% ethanolic extract of H. erinaceus demonstrated antitumor effect against colon cancer cells SW620, liver cancer cells HepG2 and Huh7, with IC50 values of 1.0 ± 0.04, 0.40 ± 0.04, and 0.50 ± 0.03 mg/mL, respectively. In addition, the 95% ethanolic‐soluble part of 50% ethanolic extract revealed cytotoxic activity against HepG2 and Huh7 cells with IC50 values of 0.35 ± 0.02 and 0.20 ± 0.01 mg/mL, respectively. On the other hand, the 95% ethanolic‐insoluble part of 50% ethanolic extract revealed cytotoxicity against HepG2 and Huh7 cells with IC50 values of 7.50 ± 0.38 and 4.50 ± 0.42 mg/mL, respectively. Moreover, the water extract of H. erinaceus displayed antitumor activity against the tested cancer cells, SW620, HepG2, and Huh7, as well as gastric cancer cells NCI‐87 and AGS, with IC50 values of 2.0 ± 0.12, 2.5 ± 0.25, 0.80 ± 0.08, 5.0 ± 0.22, and 4.97 ± 0.12 mg/mL, respectively. The 95% ethanolic‐soluble part of the fungus water extract showed antitumor activity with IC50 values (mg/mL) 2.00 ± 0.25 (HepG2 cells), 1.50 ± 0.28 (Huh7 cells), 4.50 ± 0.14 (NCI‐87 cells), and 5.10 ± 0.11 (AGS gastric cells). Whilst the 95% ethanolic‐insoluble part of the fungus water extract showed activity toward liver cancer cells HepG2 and Huh7 with IC50 4.80 ± 0.29 and 1.20 ± 0.18 mg/mL, respectively. Both compounds, 19 and 20 exhibited antitumor effects against HepG2 liver cancer cells and Caco‐2 intestinal cancer cells.
New hericenones have been reported from the dichloromethane extract of mature H. erinaceus fruiting bodies by Ruan et al. [18]. Importantly, compounds have been identified as hericenone O (21), hericenone P (22), hericenone Q (23), and hericenone R (24), alongside eight known hericenone derivatives, including hericenone C (3), hericenone D (4), hericenone E (5), hericenone F (6), hericenone G (7), hericenone H (8), [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25), and hericenone J (11). The antitumor activity of new hericenones O–R (21–24) were examined against human colorectal carcinoma cells HCT‐116 and human liver cancer cell line Hep‐G2. Hericenone Q (23) displayed a moderate and selective cytotoxicity against HCT‐116 cells with an IC50 value of 65.64 µM, as compared with 5‐FU with an IC50 value of 44.60 ± 0.22 µM. Meanwhile, it exhibited a strong antitumor activity against HepG2 cells with an IC50 value of 23.89 µM (5‐FU showed an IC50 value of 39.16 ± 5.63 µM). Hericenone R (23) displayed a weak activity against HepG2 cells with an IC50 value of 96.53 µM.
4.2. Hericenones With Neuroprotective, Anti‐Inflammatory, and Antioxidant Activities
Beyond their cytotoxic properties, many hericenones exhibit significant neuroprotective, anti‐inflammatory, and antioxidant activities. These effects are primarily mediated through the stimulation of NGF synthesis, the enhancement of neurite outgrowth, and reduction of oxidative stress and neuroinflammation, making them promising candidates for supporting neurological health. This subsection will detail the specific hericenones responsible for these effects and discuss the molecular evidence supporting their multifaceted role in protecting the central nervous system (CNS).
In a study by Kawagishi et al. [9], they reported hericenone derivatives characterized with an aldehyde and fatty acid substitution moieties, including hericenones C (3), D (4), and E (5) as seen in Figure 3. They were classified as benzyl alcohol derivatives and purified from H. erinaceus in 1991. These molecules showed beneficial therapeutic effects in dementia and related disorders via stimulating the synthesis of NGF. The in vitro assay revealed that hericenone C (3) at a concentration of 33 µg/mL stimulated NGF secretion by 10.8 pg/mL. Whilst hericenones D (4) and E (5) (33 µg/mL) stimulated synthesis of NGF by 23.5 ± 1.0 and 13.9 ± 2.1 pg/mL, respectively [9].
In 1992, the same group [24] isolated further benzyl alcohol hericenones with fatty acid side chain from H. erinuceus, that were identified as hericenones F–H (6–8). These compounds revealed stimulating effect on NGF synthesis. Apparently, hericenone H (8) (33 µg/mL) displayed a promising effect on NGF where 45.1 pg/mL of NGF was secreted into a medium in the experiment, which was four times higher than normal secretion rate. It is worth noting that the results of NGF synthesis effect of hericenone F (6) and hericenone G (7) were varied based on cultured cells' batch, as well as density of cells used in different experiments [24]. Notably, the activity of these compounds is dependent mainly on the fatty acids' nature.
In addition, hericenone D (4) was isolated in 2008 from the fungus H. erinaceus SH1 and chemically identified as 3‐(3,7‐dimethyl‐5‐oxo‐2,6‐octadienyl)‐2‐hydroxy‐6‐(hydroxymethyl)‐4‐methoxybenzaldehyde‐1′‐O‐octadecanoyl [25].
Another study by Corana et al. [26] indicated that hericenones C (3) and D (4) were found in H. erinaceus strain H.e.2 (MicUNIPV, University of Pavia, Italy) which was isolated from a sporophore collected in Italy. Hericenones C (3) and D (4) were analyzed at various growth stages, including mycelium, primordium, wild‐type, and cultivated sporophores, using HPLC–UV–ESI/MS and compared with standard compounds. Hericenones C (3) and D (4) were determined in the cultivated sporophores with 1560 and 188 µg/g, respectively, as compared to their contents in the wild type with 760 and 100 µg/g, respectively. Consequently, the contents of hericenones C (3) and D (4) were twofold higher in the cultivated fungus. Moreover, the wild type sporophores indicated that H.e.2 strain contains high content of hericenones C (3) and D (4) with 760 and 100 µg/g, respectively, compared to other Italian H.e.1 strain with 500 µg/g and less than 20 µg/g, respectively. Furthermore, at the primordium stage, an intermediate phase between mycelium and sporophore, only hericenes were detected, with no hericenones or erinacines present [26].
Further studies on H. erinaceus mushroom as reported by Ueda et al. [17] yielded three metabolites, identified as 3‐hydroxyhericenone F (9a), hericenone I (10), and hericenone J (11) (Figure 3). They were isolated from the combined ethanolic and acetonic extracts of H. erinaceus fruiting bodies. Among the isolated compounds, 3‐hydroxyhericenone F (9a) at a concentration of 1.0 and 10.0 µg/mL exhibited protective effects on Neuro‐2a cells by reversing tunicamycin (TM)‐ and thapsigargin (TG)‐induced stress on endoplasmic reticulum (ER). On the other hand, hericenone I (10), and hericenone J (11) displayed no activity [17].
3‐Hydroxyhericenone F (9a) was reported by Ueda et al. [17] as (2S,3S)‐8‐formyl‐3‐hydroxy‐5‐methoxy‐2‐methyl‐2‐(4‐methyl‐2‐oxopent‐3‐enyl)chroman‐7‐yl‐methyl palmitate. However, in 2021, Kobayashi et al. [3] revised its structure through detailed cyclization mode analysis and NMR spectroscopic studies. The revised compound, named hericenone Z (9b), was assigned as (±)‐((S*)‐7‐formyl‐2‐((R*)‐2‐hydroxy‐6‐methyl‐4‐oxohept‐5‐en‐2‐yl)‐4‐methoxy‐2,3‐dihydrobenzofuran‐6‐yl)methyl palmitate. Both structures are provided here, where the originally proposed one is (9a) and the corrected one is (9b) for readers' reference. Moreover, they obtained a synthetic 3‐hydroxyhericenone F (9c) where the stereo configuration of C3 is opposite to the original assignment of previously reported natural 3‐hydroxyhericenone F (9a). In the study by Kobayashi et al. [3], the neuroprotective activity of some synthetic hericenones against TM‐ and TG‐induced ER stress‐dependent cell death was evaluated in the murine neuroblastoma cell line (Neuro‐2a cells). Hericenone C (3), which contains a palmitoyl ester, exhibited moderate neuroprotection effect against TG‐induced ER‐stress, whereas hericenone D (4) with stearoyl moiety showed no significant activity. The neuroprotective effect of hericenone C (3) was comparable to that of hericenes A–C, indicating that the C5′‐ketone moiety is not essential for this activity. At low concentrations (3–30 µM), hericenone E (5) possessing a linoleoyl group demonstrated a modest but nonsignificant trend toward enhanced cell viability under TM‐induced ER stress conditions. The six‐membered cyclized derivatives, hericenones F (6) and H (8), demonstrated cytotoxic effects rather than exhibiting neuroprotective properties. Such findings suggest that the linoleoyl ester moiety may exert a more pronounced effect on cell viability enhancement compared to the palmitoyl ester. Notably, synthetic 3‐hydroxyhericenone F (9c) exhibited almost no neuroprotective activity. The introduction of a C3‐hydroxyl group in (9c) appeared to attenuate the cytotoxicity observed in the parent compound hericenone F (6), while not conferring significant neuroprotection. Significantly, the 5‐exo cyclization product, hericenone Z (9b) demonstrated a neuroprotective effect against TG‐induced neuronal apoptosis in concentration‐dependent manner, particularly at concentrations 30 and 100 µM.
Furthermore, hericenones C–E (3–5) have been additionally reported by Mori et al. [6] from an ethanolic extract of lyophilized powder prepared from the fresh fruiting bodies of H. erinaceus. The authors examined the NGF‐inducing properties of the ethanolic extract of H. erinaceus on 1321N1 human astrocytoma cells. Importantly, the results indicated potential stimulating activity of H. erinaceus on NGF. At a concentration of 100 µg/mL, the extract significantly increased the NGF mRNA levels. Although previous reports indicated that H. erinaceus' hericenones C (3), D (4), and E (5) at 33 µg/mL were able to promote NGF synthesis in mouse astroglial cells, they did not increase the NGF mRNA expression at 10–100 µg/mL in 1321N1 cells [6].
Mori et al. [27] provided evidence for the neuroprotective potential of H. erinaceus in a mouse model of Alzheimer's disease. They reported that oral administration of a 5% H. erinaceus diet for 23 days significantly prevented Aβ(25–35)‐induced cognitive impairment. Phytochemical analysis of the freeze‐dried mushroom identified hericenones C–E (3–5) as constituents, with HPLC quantification revealing hericenone C (3) as the most abundant (4.12 mg/g), followed by hericenone E (5) (0.49 mg/g) and hericenone D (4) (0.21 mg/g).
Another study by Zhang et al. [8] reported the isolation of a meroterpenoid, named as hericenone K (13) and 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) from the ethyl acetate‐soluble part of total ethanolic extract of H. erinaceus fruiting bodies. A 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) was a racemic mixture as indicated by circular dichroism (CD) analysis and specific optical rotation. Hence, using reversed‐phase chiral HPLC, it was separated into two enantiomers, S‐(−) and R‐(+). Similarly, hericenone K (13) was suggested as a pair of (–)‐ and (+)‐enantiomers, which was confirmed by chiral reversed‐phase HPLC, where it was resolved into two enantiomers, (−)‐ and (+)‐hericenone K. However, the pure forms were not obtained. Moreover, the neurotrophic activity was assessed using neuronal differentiation PC‐12 rat pheochromocytoma cells. At concentrations of 10 and 20 µM, (14) demonstrated no toxicity on tested cells. PC‐12 cells were treated with compounds at concentrations of 10 and 20 µM without/with 20 ng/mL exogenous NGF. All forms of (14) in combination with exogenous NGF displayed an elevation in neurite‐bearing cells comparable to those of NGF‐treated cells. When cells treated with 20 µM of different forms of (14) in combination with a 20 ng/mL of NGF, the neurite‐bearing cells were determined to be 19.96 ± 0.32%, for (±)‐racemic form of (14), 17.85 ± 0.36% for (−)‐enantiomer (14) and 21.79 ± 0.49%, for (+)‐enantiomer. These results were significantly higher than those detected for the negative control. Conversely, treatment of PC‐12 cells with compounds alone did not exert any effect on the neurite outgrowth activity. On the other hand, (13) was not evaluated in the study.
Hericenones B–E (2–5) were reported from the basidiocarps (fruiting body) of H. erinaceus. Using semi‐preparative HPLC, hericenones B–E (2–5) were purified. They were determined by comparing their mass and NMR spectral data to those previously reported [27]. Phan et al. [27] evaluated the activity of hericenones C–E (3–5) to promote neurite outgrowth. Compounds alone (without NGF) at 10–30 µg/mL concentration did not promote neurite outgrowth as demonstrated by 7.7%–9.2% neurite bearing scores. Then, the neurite outgrowth ability of hericenones in the presence of NGF was assessed. With 5 ng/mL NGF, hericenones C–E (3–5) (10 µg/mL) significantly enhanced the neurite‐bearing cells comparable to control cells treated with hericenones alone or 5 ng/mL of NGF. Importantly, hericenone E (5) induced 47% neurite outgrowth activity. Consequently, hericenones are synergistic neurotrophic compounds that promote NGF‐stimulated neurite outgrowth activity in PC‐12 cells. Moreover, the NGF levels in PC‐12 cells treated with hericenones C–E (3–5) were examined to discover their abilities to enhance NGF‐stimulated neurite outgrowth by promoting the NGF synthesis. Hericenones C–E (3–5) alone only promoted NGF synthesis by 20–57 pg/mL, while PC‐12 cells treated with 50 ng/mL of NGF secreted 157 ± 12 pg/mL. Interestingly, hericenones C–E (3–5) at a concentration of 10 µg/mL enhanced NGF secretion to 100.0 ± 1.0, 143.0 ± 9.0, and 319 ± 12.0 pg/mL, respectively, in combination with 5 ng/mL of NGF. Hericenone E (5) revealed a significant effect on NGF biosynthesis activity with 319 ± 12 pg/mL which was the highest among other hericenones with two times higher than that of the positive control. This effect might be mediated through signaling pathways, including extracellular signal‐regulating kinases (ERK1/2) and protein kinase (Akt) to promote neuronal differentiation and development. In another study, hericenones C–E did not increase NGF mRNA expression at 10–100 µg/mL in 1321N1 human astrocytoma cells and primary cultured rat astroglial cells [6, 9]. NGF is important for the development and differentiation of neurons in the CNS. Hence, healthy NGF secretion in the CNS is of great importance. H. erinaceus demonstrated neuroprotective properties in the treatment of ischemic brain damage in mice via induction of NGF biosynthesis. Consequently, hericenones C–E (3–5) could be utilized as promising therapeutic agents for neurodegenerative conditions [27].
In a patent published in 2018 by Stamets [28], the combination of psilocybin or psilocin or mushrooms extracts containing psilocybin with hericenones, particularly hericenones C–H (3–8) or erinacines, and vitamin B3, help in neuronal generation and cognition. Vitamin B3 (niacin) is a neural anti‐inflammatory which has a positive effect on promoting neuronal functions. It also stimulates nerve endings and thus it was suggested to improve the neurogenic properties of hericenones, psilocybin, psilocin, and erinacines. A proposed formulation with herbs or constituents to improve neurological function without causing toxicity include a combination of 1 mg psilocin or psilocybin, 50 mg hericenones or erinacines, 200 mg niacin per day, 199 mg extract of H. erinaceus mycelium or fruit bodies, and 100 mg plant extracts with neurogenic properties. This formulation is administered as an ingestible capsule in a 550 mg dose. Other formulations proposed to promote neurogenesis in a 70 kg person (154 lb) contain components such as psilocin or psilocybin (0.1–0.6 mg), hericenones or erinacines (1–20 mg), and niacin (1–50 mg). Additional neurogenic formulations have the same composition but contain variable concentrations, including hericenones ranging from 1 to 200 mg.
A study on an Italian H. erinaceus strain (He.1) employed high‐performance liquid chromatography–ultraviolet–electrospray ionization–mass spectrometry (HPLC–UV–ESI–MS) to analyze a 70% ethanolic extract of its mycelium and sporophores [29]. The analysis confirmed the presence of hericenone C (3) at 500 µg/g and hericenone D (4) at a trace level (< 20 µg/g) by comparison with standards. In a related in vivo experiment, oral supplementation with H. erinaceus for 2 months was found to restore memory recognition in a model of age‐related disease. This cognitive improvement was supported by enhanced neurogenesis, evidenced by increased expression of proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) in the hippocampus and cerebellum of treated frail mice [29].
Another related study utilized HPLC–UV–ESI–MS for the determination of hericenone C (3), hericenone D (4) in Italian H. erinaceus (He.1) [30]. The extract was found to contain 500 µg/g of hericenone C (3) and 20 µg/g of hericenone D (4). The effect of a 60 day oral administration of standardized H. erinaceus extract, containing a known amount of erinacine A, hericenone C (3), hericenone D (4), and l‐ergothioneine, on locomotor frailty and cerebellum of aged mice. The mixture of ethanolic extracts of H. erinaceus' sphorophore and mycelium solubilized in water, was administered as 1 mg supplement/mouse daily, and this dose mimic the oral supplementation in humans 1 g/day. In the study, locomotor functions were compared between healthy aging and frail mice. Cerebellar volume and cytoarchitecture, as well as inflammatory and oxidative stress, were evaluated with a focus on senescent frail animals. H. erinaceus supplementation was able to recover the aged‐related decline of locomotor functions. Histopathological and immunocytochemical analyses supported neuroprotective activity of H. erinaceus, revealing mitigated cerebellar degeneration, including cerebellum volume loss—a key factor implicated in age‐related declines, and reduced molecular layer. In addition, H. erinaceus decreased inflammation and oxidative stress, while upregulating a key longevity factor and neuroprotective molecule. Since IL‐6 and tumor necrosis factor (TNF) are attributed to neurodegeneration and negatively affecting Purkinje neuron function and survival, the results revealed a significant decline of IL‐6 in He.1 mice group compared to untreated animals. This accompanied by a significant decline of glial fibrillary acidic protein (GFAP) and astrocytes in He.1 treated mice. The results also indicated that He.1 treated mice showed a significant elevation of vascular endothelial growth factor (VEGF) expression levels, particularly in Purkinje cells. The VEGF is a significant player as a neurogenic, neurotrophic, and neuroprotective molecule in the CNS [30].
A randomized, double‐blind, placebo‐controlled, parallel‐group study was conducted to evaluate the effects of 84‐day supplementation with H. erinaceus fruiting bodies (0.8 g/day) on cognitive function. The results demonstrated that supplementation significantly improved cognitive performance. The authors propose that bioactive constituents, such as hericenones, may confer these benefits by supporting CNS neurons. These findings suggest that oral H. erinaceus supplementation is a safe and potential strategy for dementia prevention [7].
Tamrakar et al. published a study describing the deacetylation of hericenone C (3) to get a deacylhericenone (18) with a potent neuroprotective activity compared to the parent compound [31]. Hericenone C (3) is a meroterpenoid derivative with palmitic acid side chain. It is reported as NGF stimulatory agent with beneficial neuroprotective properties. The freeze‐dried powder of fruiting bodies of H. erinaceus was extracted with ethanol, and hericenone C (3) was obtained from the n‐hexane‐soluble part. The fatty acid moiety in the structure is liable to lipase enzyme hydrolysis in in vivo metabolic conditions. Hence, 2 mg of hericenone C (3) from the extract in 100 µL acetone solution was treated with lipase enzyme (50 U/mL). The deacetylated compound, deacylhericenone (18), was isolated and determined by liquid chromatography–quadrupole time‐of‐flight mass spectrometry (LC–QTOF–MS) and 1H NMR analyses. Evaluation of the neuroprotection properties of both compounds, (3) and (18), revealed that the mRNA expression levels and H2O2‐induced oxidative stress protection was improved when treating with a deacetylated compound. The bioactivity of H. erinaceus ethanolic extract, hericenone C (3) and deacylhericenone (18) on the mRNA expression levels of brain‐derived neurotrophic factor (BDNF) in 1321N1, SH‐SY5Y, and Caco‐2 cells were evaluated. The ethanolic extract at 100 µg/mL increased the mRNA expression levels by more than 1.5‐fold in the experiment. Both (3) and (18), at 12.5 µg/mL, exhibited significant increase in expression levels in Caco‐2 cells by two‐ and threefold. Only (18) significantly increased the mRNA expression in SH‐SY5Y cells by 1.5‐fold. Moreover, the protection activity of the ethanolic extract, (3), and (18) on H2O2‐stimulated oxidative stress was evaluated in 1321N1 cells. The ethanolic extract at 5 µg/mL exhibited 72.6% cell viability. At concentrations ranged between 1.6 to 12.5 µg/mL, hericenone C (3) did not protect against oxidative stress. Conversely, deacylhericenone (18) (1.6–12.5 µg/mL) displayed a protection in a dose‐dependent manner. At 12.5 µg/mL of deacylhericenone (18), the cell viability reached 78.4%. Consequently, the bioactivity of deacylhericenone (18) is improved owing to the removal of the fatty acid side chain from hericenone C (3) [31].
A recent study used a computational approach combining machine learning with structural modelling to discover new acetylcholinesterase (AChE) inhibitors from H. erinaceus. The study utilized training of deep learning neural network using the enzyme inhibitory assays data set revealing which compound is active on AChE enzyme. Furthermore, molecular docking simulations were carried out to validate compounds with proposed AChE activity. Hence, hericenone B (2) was proposed as anti‐AChE candidate according to analysis. The results indicated that hericenone B (2) displayed an averaged “active” probability score of 0.9283 ± 0.0876. In addition, molecular dynamics simulations (50 ns) between the target protein (AChE) and hericenone B (2), were assessed and compared with donepezil and galanthamine. The binding free energy of hericenone B (2), was driven by van der Waals interactions. The total AChE binding free energy of hericenone B (2) was −151 ± 16 kJ/mol. Hericenone B (2) exhibited binding mechanisms resembling donepezil and galanthamine with strong binding energy. Thus, based on combined deep learning and molecular modelling analysis, hericenone B (2) has been identified as a potential AChE inhibitor [32]. In another study, Chen et al. [22] investigated the anti‐AChE activity of an ethanolic extract H. novae‐zealandiae and its constituent, hericenone C (3). The extract showed AChE inhibition activity reaching 40.34% when the concentration increased from 0.48 to 3.0 mg/mL. The IC50 values obtained were 5.19 ± 0.49 mg/mL for ethanolic extract and more than 26 µM for hericenone C (3).
In their efforts to discover anti‐inflammatory constituents from Korean natural sources, Noh et al. conducted a bioassay‐guided investigation of a methanolic extract obtained from the fruiting bodies of H. erinaceus. The study afforded five benzyl alcohol molecules [33]. Based on biological activity screening, the active n‐hexane‐ and dichloromethane‐soluble fractions that showed inhibition effect on nitric oxide (NO) production in lipopolysaccharide (LPS)‐treated RAW264.7 macrophages were chemically investigated to afford hericenone D (4), hericenone E (5), and hericenone F (6). Hericenone E (5) exhibited marked inhibition of LPS‐induced NO release at a concentration of 100 µg/mL. Moreover, treatment of macrophage cells induced by LPS with hericenone E (5) displayed a marked decline in the production levels of prostaglandin E2 (PGE2) and NO, proinflammatory mediators, in concentration dependent manner, revealing IC50 values 85.20 ± 0.30 and 78.95 ± 4.73 µM, respectively. It is worth noting that 100 µM of hericenone E (5) did not exhibit any cytotoxicity on the viability of macrophage cells [33]. Furthermore, the anti‐inflammatory molecular mechanism of hericenone E (5) was examined through evaluation of its suppression effect on phosphorylation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and activator protein‐1 (AP‐1) subunits, transcription factors implicated in inflammatory response. In a time‐dependent manner, hericenone E (5) suppressed phosphorylation of NF‐κB and AP‐1, by inhibiting phospho‐p50 and phospho‐c‐Fos at 60 min [33]. Hence, hericenone E (5) could be used as a potential therapeutic strategy for the treatment of inflammatory diseases [33].
In a study by Lee et al. [34], extracts from several Hericium strains were evaluated for their anti‐inflammatory potential. The dichloromethane‐soluble fraction was subjected to chromatography separation yielding hericenones C (3), D (4), and F (6). Their concentrations were quantified via HPLC/UV. When evaluated on LPS‐ and interferon‐gamma (IFN‐γ)‐stimulated RAW264.7 macrophages, all extracts (200 µg/mL) suppressed NO synthesis, with Korean forest research institute (KFRI)‐1093 strain exhibiting strongest inhibition (60.5% NO production). Quantification of hericenones content showed that the distribution varied by strain. The Norugungdenglee‐2 strain contained the highest level of hericenone C (8.29 mg/g), KFRI‐1453 had the most hericenone D (4.66 mg/g), and the highly active KFRI‐1093 strain was the richest source of hericenone F (5.41 mg/g) [34].
Hericenone F (6), among other metabolites, was reported from the 95% ethanolic extract obtained from oven‐dried mature H. erinaceus fruiting bodies, collected in China. The anti‐inflammatory activity of hericenone F (6) toward production of pro‐inflammatory mediators, including TNF‐α, IL‐6, and NO, in LPS‐induced RAW264.7 cells, was investigated. The results demonstrated that hericenone F (6) displayed a moderate inhibition activity on the secretion of TNF‐α, IL‐6, and NO with IC50 values of 62.46, 48.50, and 76.16 µM, respectively [10].
The anti‐nociceptive activity of hericenone C (3) was evaluated intraperitoneally at doses 2.5, 5, and 10 mg/kg. In a dose‐dependent manner, (3) inhibited the pain in second phase of formalin‐induced nociception, particularly with significant effect at 10 mg/kg. Furthermore, a luciferase assay was conducted to determine the hericenone C (3) effect on P65 activation, a key factor that regulate inflammation. Hericenone C (3) was able to significantly inhibit luciferase activity with a reduction in phosphorylation of P65. Consequently, (3) inhibits P65 activation leading to anti‐inflammatory effect. In addition, pretreatment of RAW264.7 cells with hericenone C (3) (40 µM) significantly suppressed the mRNA expression of formalin‐induced IL‐6, an inflammatory cytokine. Moreover, hericenone C (3) reduced the number of CD11c‐positive cells, a marker of proinflammatory cells, which further supports the anti‐inflammatory effect via inhibiting the proinflammatory cells' activation. This study has also demonstrated that hericenone C (3) inhibited the P65 activation of CD11b/CD11c‐positive cells in the paw of formalin‐treated mice [35].
Chen et al. evaluated the antioxidant activity of an ethanolic extract of H. novae‐zealandiae. The extract exhibited antioxidant activities against DPPH with IC50 34.45 ± 1.12 µmol TE/g, ferric reducing ability of plasma (FRAP) with IC50 29.57 ± 0.90 µmol TE/g, and ABTS with IC50 58.87 ± 1.78 µmol TE/g. However, hericenone C (3) was not evaluated because of limited obtained amount [22]. In another study published in 2021, HPLC analysis of H. erinaceus extracts collected at different growth periods, 14, 21, and 28 days revealed similar peaks and retention times of bioactive metabolites. Hericenone C (3) was detected, and the results indicated highest content of hericenone C (3) characterized at 14 days growth with 1.23 ± 0.10 mg/g dried sample. Meanwhile, its content at 21 and 28 days were 0.73 ± 0.09 and 0.48 ± 0.01 mg/g, respectively. Furthermore, the antioxidant activity toward DPPH and ABTS of 21‐day sample was potent than samples collected at 14 and 28 days, with IC50 63.30 mg extract/mL [36].
4.3. Hericenones With Antiplatelet Activity
The pharmacological effect of hericenones extends beyond neuroprotection and cytotoxicity to include beneficial properties in cardiovascular events. Among these, antiplatelet activity represents a highly important function. Uncontrolled platelet aggregation is a critical event in cardiovascular diseases, and discovering novel inhibitors is a key therapeutic goal. Research on H. erinaceus has revealed that certain hericenones possess antiplatelet activity, with hericenone B (2) exhibiting particularly potent and selective action [37]. This subsection focuses on the antiplatelet activity of hericenones, particularly hericenone B (2), which has emerged as a uniquely effective and selective antiplatelet agent, and explores the structural features that underpin this activity.
The antiplatelet bioassay‐guided isolation study by Mori et al. [37] has reported hericenone B (2), as well as hericenones C–E (3–5) from the ethanolic extract of fresh fruiting bodies of H. erinaceus. Hericenone B (2) demonstrated a potent antiplatelet activity induced by collagen. Moreover, the total inhibition of platelet aggregation was observed for hericenone B (2) at a concentration of 30 µM. In a concentration‐dependent manner, hericenone B (2) inhibited aggregation of human platelets with an IC50 value of 3.0 µM. Besides, hericenones C–E (3–5) at a concentration 100 µM did not exhibit antiplatelet activity. Hericenone B (2) selectively inhibits collagen‐induced platelet aggregation by targeting the upstream suppression of arachidonic acid release in integrin α2/β1 signaling [37]. Hence, hericenone B (2) might be used as a novel natural‐derived molecule for antithrombotic therapy. Importantly, hericenone molecules possessing fatty acid moiety may not exhibit platelet aggregation inhibition activity. Furthermore, the presence of γ‐lactam and N‐substitution moieties may be responsible for the antithrombic activity of hericenone B (2) [37].
4.4. Hericenones with Anti‐Obesity Activity
Building on clinical observations that H. erinaceus can alleviate depression and anxiety in menopausal women, subsequent research has explored its potential to address other menopausal‐related conditions, particularly weight gain. This subsection examines the anti‐obesity activity of Yamabushitake in ovariectomized mice—a model for postmenopausal metabolism—and discusses the specific hericenones identified as potentially active compounds responsible for this effect [38].
The anti‐obesity effect of H. erinaceus in menopause was analyzed. The powdered H. erinaceus increased levels of lipids in excreted faecal matter. In addition, the in vitro evaluation displayed that the ethanolic extract and n‐hexane‐soluble fraction at concentrations of 400 µg/mL have inhibitory effect on lipase enzyme, consequently contributing to the anti‐obesity effect of H. erinaceus during menopause. This study has led to the isolation of lipase‐inhibitory metabolites from the extract, including hericenone C (3), hericenone D (4), hericenone F (6), and hericenone G (7). The in vivo studies with 0.09 g/day H. erinaceus powder indicated that the fruiting bodies of H. erinaceus significantly reduced white adipose tissue in subcutaneous and visceral fats, fatty tissue amounts surrounding kidney and uterus, and plasma levels of total cholesterol and leptin, as well as an increase in adiponectin. Thus, H. erinaceus has a positive impact on hyperlipidaemia and obesity, particularly in menopausal women [38]. Moreover, in the study, a significant inhibition of lipase enzyme was observed for the ethanolic extract and n‐hexane‐soluble fraction. Importantly, the utmost lipase‐inhibition activity was noted for the n‐hexane fraction. Hence, bio‐guided fractionation based on lipase‐inhibition activity has led to the purification of four metabolites that were determined as hericenone C (3), hericenone D (4), hericenone F (6), and hericenone G (7). Among them, hericenone C (3) at a concentration of 400 µg/mL showed a potent lipase‐inhibition activity revealing about 70% inhibition. Furthermore, the HPLC analysis revealed that the ethanolic extract has 18.5 µg/g of hericenone C (3), 332.2 µg/g of hericenone D (4), 7.3 µg/g of hericenone F (6), and 7.9 µg/g of hericenone G (7). Whilst the n‐hexane fraction has 23.1 µg/g of hericenone C (3), 416.1 µg/g of hericenone D (4), 8.4 µg/g of hericenone F (6), and 8.6 µg/g of hericenone G (7). From SAR perspective, the hydrophilicity of compounds is attributed to its high lipase‐inhibition properties. Hence, the activity of hericenone C (3) is likely to be more than hericenone F (6), hericenone D (4), and hericenone G (7) [38].
4.5. Hericenones With Antidiabetic Activity
Diabetes mellitus, a prevalent global metabolic disorder characterized by hyperglycemia, is managed by inhibiting the carbohydrate‐digesting enzyme α‐glucosidase to control postprandial blood glucose [39]. Given the search for natural therapeutic agents, the edible and medicinal mushroom H. erinaceus has emerged as a promising candidate due to its hypoglycemic properties [40]. This subsection focuses on the antidiabetic potential of specific hericenones, examining their isolation from H. erinaceus based on α‐glucosidase inhibitory activity and their characterization through biochemical and molecular docking analyses.
Hericenones C–H (3–8) were reported from the petroleum ether extract of fruiting bodies of H. erinaceus. Chromatographic separation using silica gel, ODS, and Sephadex LH‐20, and semi‐preparative HPLC, were applied for the purification of these compounds. Hericenones C–H (3–8) were confirmed in the study by comparing their spectroscopic data with those reported in the literature. Hericenones C–H (3–8) (6.25–100 µM) were assessed for their inhibition activities toward α‐glucosidase from small intestinal mucosa of rat with substrates, including PNPG, sucrose, and maltose. Hericenones C (3), E (5), F (6), and G (7) were reported to display α‐glucosidase inhibition on p‐nitrophenyl α‐d‐glucopyranoside (p‐NPG), sucrose, or maltose. Hericenone C (3) displayed inhibition activities against p‐NPG, sucrose, and maltose with IC50 values of 21.9, 13.5, and 15.3 µM, respectively. Whilst hericenone E (5) displayed inhibition activities with IC50 values of 23.3, 42.5, and 25.2 µM, for p‐NPG, sucrose, and maltose, respectively. Hericenone F (6) demonstrated inhibition activity against p‐NPG, sucrose, and maltose with IC50 values of 45.3, 67.1, and more than 100 µM, respectively. Hericenone G (7) demonstrated strongest activity with IC50 values of 15.2, 12.6, and 33.1 µM, against p‐NPG, sucrose, and maltose, respectively. Comparing to other constituents in mushroom, the ketonization at C‐5′ enhances the α‐glucosidase inhibitory activity. Furthermore, the potent activity of hericenone C (3) and E (5) than that of hericenone D (4), and the potent effect of hericenone F (6) and G (7) than that of hericenone H (8) suggested that the structure of C‐7 fatty acid moiety is greatly influenced the activity [41].
Another study by Lee et al. [39], chromatographic purification of the n‐hexane‐soluble part of dried fruiting bodies of H. erinaceus, yielded hericenone J (11), 4‐[3′,7′‐dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methyoxybenzylalcohol (17), hericenone D (4), and hericenone E (5). The α‐glucosidase inhibitory effect of the isolated hericenones was assessed. Compounds (17) and (4) displayed strong inhibition of α‐glucosidase activity with IC50 values of 7.5 and 15.5 µM, respectively. Furthermore, the molecular docking studies indicated that the docking scores of (17) and (4) were 7.840 and 9.953. Molecular docking revealed that these hericenones inhibit α‐glucosidase by forming key hydrogen bonds within the enzyme's active site. Compound (17) forms hydrogen bonds with residues Gln182, Arg446, Asp215, Asp69, Glu277 with lengths of 2.26, 2.14, 2.20, 1.92, and 2.38 Å. In addition, hericenone D (4) interacts with Asp307 with length of 2.19 Å., while hericenone E (5) showed a docking score of 7.586 and forms hydrogen bond interaction with Gln353, Arg442, and Glu411 with lengths of 2.22, 2.28, and 2.53 Å. These consistent interactions with critical catalytic residues explain the observed inhibitory activity [39]. Compound, 4‐[3′,7′–dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methyoxybenzylalcohol (17) was previously reported by Miyazawa et al. [42] from the ethyl acetate‐soluble part of H. erinaceus fruiting bodies. Compound (17) was evaluated for α‐glucosidase inhibitory activity, where it displayed inhibition activity with an IC50 value of 12.5 ± 1.3 µM. In addition, Arnone et al. [43] had already identified the same compound as a product of methanolysis of hericenes A–C in their study.
4.6. Hericenones With Antibacterial Activity
While primarily investigated for their neuroprotective and anticancer properties, certain hericenones have also been explored for their antimicrobial potential. This exploration is often proposed based on structure similarity to known antibiotics. A key example is the evaluation of a specific hericenone derivative, prompted by its similarity to mycophenolic acid, to determine if it shares similar bioactive properties. The following section details the findings of this investigation into the antibacterial activity of hericenones. Due to its structural similarity to mycophenolic acid, compound 25 (previously discussed in Section 4.1) was evaluated for antibacterial activity by Ma et al. [1]. When tested against a panel of bacterial strains—including Staphylococcus aureus, Escherichia coli, and several Bacillus species—it displayed only weak effects at a concentration of 1 mg/mL. The authors proposed that this lack of potency could be due to the cleavage of an essential γ‐lactone ring in its structure [1].
Beyond antibacterial properties, the biological profile of hericenones has been further explored in other therapeutic areas. In a 2015 study aimed at discovering bioactive molecules, Noh et al. [44] isolated hericenone D (4), hericenone E (5), and hericenone F (6) from a methanolic extract of H. erinaceus fruiting bodies. The isolated compounds were subsequently tested for their inhibitory effects on cellular senescence in human primary cells (HDFs and HUVECs). Despite this targeted investigation, the hericenones failed to show promising anti‐senescence activity.
Collectively, this review systematically covers the current knowledge on 25 hericenones (1–25) isolated from H. erinaceus, detailing their diverse structural features and multifaceted pharmacological profiles. Collection of the current data reveals several key trends, highlights research gaps, and points toward promising future directions. A key point from the literature is the influence of chemical structure on bioactivity.
Regarding neuroprotective and NGF‐stimulating activity, the activity is dependent on the nature of the side chain. Compounds with fatty acid esters, such as hericenones C (3, palmitoyl), D (4, stearoyl), and E (5, linoleoyl), demonstrate the ability to stimulate NGF synthesis and promote neurite outgrowth [9, 45]. Notably, the lipophilicity of the side chain influences both bioavailability and activity, as evidenced by the enhanced neuroprotective and antioxidant effects of deacylhericenone (18) compared to its parent molecule, hericenone C (3) [31]. Furthermore, six‐membered cyclized derivatives, hericenones F (6) and H (8), demonstrated cytotoxicity rather than exhibiting neuroprotective properties [3]. Moreover, the cyclization is critical; six‐membered chromone‐type hericenones such as F (6) and H (8) exhibit cytotoxicity, whereas the five‐membered cyclization in hericenone Z (9b) retains neuroprotection [3].
With regard to cytotoxic and antiproliferative activity, the potency in this area appears attributed to specific functional groups. The presence of an N‐substituted γ‐lactam moiety, as in hericenone B (2), is associated with significant cytotoxicity against HeLa cells [5]. Similarly, isohericenone (16) and other isoindolinone derivatives showed potent antitumor activity against various cancer cell lines suggesting this heterocycle is a significant feature for anticancer development [14, 21].
For α‐glucosidase inhibition, the ketone at C‐5′ position of geranyl side chain seems to enhance activity, as seen in the superior potency of hericenones C (3) and E (5) [41]. In addition, the structure of C‐7 fatty acid moiety plays a modulating role. Conversely, for lipase inhibition, which underlies anti‐obesity effects, higher hydrophilicity may be essential, as suggested by the potent activity of hericenone C (3) [38].
While hericenones C–E (3–5) stimulate NGF protein secretion in mouse astroglial cells, they fail to upregulate NGF mRNA in human astrocytoma cells [6]. This variable effects on NGF synthesis suggests a complex, post‐transcriptional mechanism of action. Elucidating this mechanism is a critical area for future research. Furthermore, there is an imbalance between in vitro evidence and in vivo or clinical validation. While numerous mechanisms, such as apoptosis induction, anti‐inflammatory signaling via NF‐κB/AP‐1, and enzyme inhibition, have been proposed based on cellular and computational studies, these remain to be confirmed in animal models. The promising results of the clinical trial on cognitive improvement [7] is a step in the right direction, but it attributes the effects generally to H. erinaceus supplementation without directly confirming the role or pharmacokinetics of individual hericenones.
The activity of many hericenones, particularly the fatty acid esters, is likely limited by poor bioavailability. Future studies should focus on assessing their absorption, distribution, metabolism, and excretion (ADME) profiles. The finding that deacylation enhances activity [31] also opens the door for prodrug strategies or the design of analogs with improved pharmacokinetic properties. Importantly, for hericenones to be developed as nutraceuticals or therapeutics, standardized extracts with quantified levels of active hericenones are essential. Future clinical trials should aim to correlate specific hericenone content with observed health outcomes.
To sum up, the hericenones from H. erinaceus exhibit diverse pharmacological properties, including neuroprotection (NGF stimulation, neurite outgrowth enhancement), anti‐inflammatory effects (NF‐κB/AP‐1 suppression, cytokine inhibition), anticancer activity (cytotoxicity against HeLa, HL‐60, and HepG2 cells), antiplatelet aggregation (via integrin α2/β1 signaling inhibition), and metabolic regulation (α‐glucosidase and lipase inhibition). Key compounds such as hericenone B (2) (antithrombotic), hericenone E (5) (potent NGF induction), and deacylhericenone (18) (enhanced neuroprotection) highlight their therapeutic potential for neurodegenerative diseases, inflammation, cancer, and metabolic disorders. Structural modifications, particularly fatty acid side‐chain alterations, further optimize bioactivity, supporting their development as lead compounds for drug discovery. Future research should focus on mechanistic pathways, clinical validation, and structural optimization to harness their full pharmacological potential.
5. Isolation of Hericenones
Hericenones, bioactive secondary metabolites from H. erinaceus, have been isolated using various extraction and chromatographic techniques. Common extraction solvents include methanol, ethanol, acetone, dichloromethane, and ethyl acetate, often followed by partitioning with water and organic solvents. Purification typically involves multiple chromatographic steps, such as silica gel column chromatography (CC), Sephadex LH‐20 CC, reversed‐phase C18 columns, and preparative HPLC with gradient or isocratic elution (e.g., methanol–water and acetonitrile–water mixtures). Of note, based on the authors' experience, we recommend an isopropanol–methanol mixture for efficient purification of hericenones due to its balanced polarity and improved solubility of these compounds [18].
Early studies isolated hericenones A (1) and B (2) through a multi‐step process of acetone extraction, silica gel chromatography, and recrystallization [5]. Subsequent research expanded the known compounds, identifying hericenones C─H (3–8) via techniques like preparative TLC and ODS‐HPLC [9, 24, 46]. Later, hericenones B–E (2–5) were obtained from ethanolic extracts that were partitioned with organic solvents including ethyl acetate or chloroform, and purified using silica gel and preparative HPLC. Later studies isolated hericenones F–R (6–24) and other derivatives using advanced techniques, including flash chromatography such as medium pressure liquid chromatography (MPLC), Biotage high‐performance flash chromatography (HPFC) and semi‐preparative HPLC [1, 8, 15, 17, 18, 20]. These methods highlight the reliance on solvent partitioning repeated CC, and HPLC for isolating structurally diverse hericenones.
It is important to note that the aldehyde group in hericenones oxidizes easily upon exposure to air or chemicals, converting them into carboxylic acids. To preserve their native structure and bioactivity, careful handling under controlled conditions is essential.
6. NMR Features of Hericenones
In this review, we have systematically collected and compiled all available NMR data on hericenones from the literature to present a comprehensive analysis of these compounds. Our compilation includes complete 1H and 13C NMR spectra, thereby establishing clear structural benchmarks for hericenones. This consolidated dataset not only enables precise identification of these compounds but also serves as a valuable resource for researchers across various fields of natural product chemistry. All NMR data cited in this work, including the specific deuterated solvents used for measurement, such as deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (DMSO‐d 6), and deuterated chloroform (CDCl3), have been reproduced exactly as reported in the original publications, without modification or reinterpretation. Any discrepancies or inaccuracies are solely the responsibility of the original authors; we assume no liability for such errors.
Hericenones A (1) and B (2), reported for the first time by Kawagishi et al. [5] were elucidated using NMR spectroscopy, IR, and mass spectrometry. Hericenone A (1) features a phthalide core with a penta‐substituted phenyl ring. Hericenone B (2) shares a similar phenolic framework but incorporates a phenylethyl substituent. Both compounds exhibit methoxy and methyl groups, but structural divergence arises from the phthalide (1) versus isoindolinone (2) core and the presence of a phenylethyl group in (2). Key distinctions in coupling constants, carbonyl shifts, and NOESY data clarified their structures, with (1) defined as 6‐[(2′E)‐3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl)]‐7‐hydroxy‐5‐methoxyphthalide and (2) as 6‐[(2′E)‐3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl)‐7‐hydroxy‐5‐methoxy‐3‐(2″‐phenylethyl)‐1‐isoindolinone, as reported by Kawagishi et al. [5].
Based on chemical synthesis‐driven structural revision, hericenone A was reassigned as compound 1a, a conclusion supported by the analysis of spectral data. As reported by Rao and Reddy [15], the initial structural assignment (1) was revised because the aromatic proton in hericenone A appeared at δ 6.97, a chemical shift more consistent with the isomeric structure 1a. Further evidence proofed from the IR spectrum, which exhibited a carbonyl stretch at 1760 cm−1 indicating a non‐hydrogen‐bonded phthalide ketone, a feature compatible with structure 1a. Definitive confirmation was achieved through total synthesis, as the synthesized methyl ether of 1a had spectral data distinct from that of natural hericenone A (1), thereby favouring the revised structure. Thus, the structure of hericenone A (1) was revised via chemical synthesis to (E)‐5‐(3,7‐dimethyl‐5‐oxoocta‐2,6‐dien‐1‐yl)‐4‐hydroxy‐6‐methoxyisobenzofuran‐1(3H)‐one (1a) [15]. Similarly, the structure of hericenone B (2) was corrected to the carbonyl regioisomer (2a) based on the total synthesis of eight compounds [16]. This reassigned structure (2a) was reported as a compound named isohericenone (16) by Kim et al. [21]. For reader reference, we have maintained the same numbering system used by Kim et al. [21] for the phenylethyl substituent attached to the isoindolin‐1‐one moiety. The NMR data of hericenones A (1), B (2), and isohericenone (16) are shown in Table 1.
TABLE 1.
NMR data of hericenones A (1), B (2), and isohericenone (16).
| 1H NMR data (multiplicity, J in Hz) | 13C NMR data | |||||
|---|---|---|---|---|---|---|
| Position | Hericenone A (1) a | Hericenone B (2) a | Isohericenone (16) | Hericenone A (1) a | Hericenone B (2) a | Isohericenone (16) |
| 1 | — | — | — | 171.86 | 168.94 | 169.9 |
| 3 | 5.25 (s) | 4.20 (s) | 4.17 (s) | 68.31 | 48.28 | 48.6 |
| 3a | — | — | — | 133.63 | 132.85 (or C‐4‴) | 121.2 |
| 4 | 6.97 (s) | 6.96 (s) | — | 98.45 | 97.69 | 150.1 |
| 5 | — | — | — | 159.18 (or C‐7) | 158.48 (or C‐7) | 120.7 |
| 6 | — | — | — | 121.35 | 118.48 | 159.3 |
| 7 | — | — | 6.86 (s) | 157.48 (or C‐5) | 156.81 (or C‐5) | 96.5 |
| 7a | — | — | 125.80 (or C‐2′) | 122.00 | 131.1 | |
| 1′ | 3.59 (d, 6.41) | 3.56 (d, 6.74) | 3.45 (d, 7.5) | 23.32 | 23.09 | 22.5 |
| 2′ | 5.30 (t, 6.41) | 5.30 (t, 6.74) | 5.31 (d, 7.5) | 125.02 (or C‐7a) | 126.51 | 127.3 |
| 3′ | — | — | — | 128.22 | 128.70 | 129.4 |
| 4′ | 3.18 (s) | 3.14 (s) | 2.99 (s) | 54.40 | 54.65 | 54.9 |
| 5′ | — | — | — | 199.08 | 198.98 | 200.9 |
| 6′ | 6.09 (s) | 6.08 (s) | 6.13 (s) | 123.05 | 123.01 | 122.6 |
| 7′ | — | — | — | 150.61 | 150.70 | 156.3 |
| 8′ | 1.91 (s) | 1.88 (s) | 1.81 (s) | 27.82 | 27.76 | 26.5 |
| 3′‐CH3 | 1.81 (s) | 1.81 (s) | 1.74 (s) | 17.18 | 17.00 | 15.4 |
| 7′‐CH3 | 2.17 (s) | 2.16 (s) | 2.07 (s) | 21.06 | 20.94 | 19.6 |
| 1″ | — | 3.84 (t, 7.33) | 3.84 (t, 7.5) | — | 44.21 | 44.2 |
| 2″ | — | 2.97 (t, 7.33) | 2.97 (t, 7.5) | — | 34.90 | 34.4 |
| 3″ | — | — | — | — | — | 138.9 |
| 4″, 8″ | — | — | 7.24 (m) | — | — | 128.5 |
| 5″, 7″ | — | — | 7.26 (m) | — | — | 128.4 |
| 6″ | — | — | 7.21 (m) | — | — | 126.3 |
| 1‴ | — | — | — | — | 138.76 | — |
| 2‴ | — | 7.20 — 7.26 (m) | — | — | 128.61 | — |
| 3‴ | — | — | — | — | — | |
| 4‴ | — | — | — | 132.20 (or C‐3a) | — | |
| 5‴ | — | — | — | — | — | |
| 6‴ | — | — | — | 128.61 | — | |
| OCH3 | 3.89 (s) | 3.84 (s) | 3.84 (s) | 56.21 | 56.21 | 55.1 |
| Solvent | CDCl3 | CDCl3 | CD3OD | CDCl3 | CDCl3 | CD3OD |
| Reference | [5] | [21] | [5] | [21] | ||
The NMR features of hericenones C (3), D (4), and E (5), reveal structurally related phenolic esters with distinct fatty acid components. All three compounds share a common phenolic core featuring a formyl group, methoxy substitutions, and a penta‐substituted phenyl ring. Key distinctions arise from the ester‐linked fatty acid chains: hericenone C (3) contains a palmitate (16:0) chain, hericenone D (4) has a stearate (18:0) chain, hericenone E (5) features a linoleate (18:2Δ9,12) ester, marked by olefinic protons (δ 5.34, m) and allylic methylene shifts (δ 2.78, dd, J = 6.60, 5.87 Hz). Methanolysis yielded methyl palmitate/stearate/linoleate, validating ester linkages. These NMR data, combined with HR–FAB–MS and IR, established their structures as 4‐(3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl)‐2‐formyl‐3‐hydroxy‐5‐methoxybenzyl esters with variable fatty acid chains [9]. Their 1H NMR and 13C NMR data are shown in Tables 2 and 3.
TABLE 2.
1H NMR data of hericenones C‐E (3–5), hericenone L (15), deacylhericenone (18), [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25).
| 1H NMR data (multiplicity, J in Hz) | ||||||
|---|---|---|---|---|---|---|
| Position | Hericenone C (3) | Hericenone D (4) | Hericenone E (5) | Hericenone L (15) | Deacylhericenone (18) | (25) |
| 6 | 6.53 (s) | 6.53 (s) | 6.53 (s) | 6.50 (s) | 6.52 (s) | 6.54 (s) |
| 7 | 5.32 (s) | 5.32 (s) | 5.32 (s) | 5.22 (s) | 4.95 (s) | 5.18 (s) |
| 8 | 10.11 (s) | 10.11 (s) | 10.11 (s) | 10.20 (s) | 10.20 (s) | |
| 1′ | 3.40 (d, 7.33) | 3.40 (d, 7.33) | 3.40 (d, 7.32) | 3.88 (d, 7.2) | 3.37 (d, 7.42) | 3.90 (d, 7.2) |
| 2′ | 5.32 (t, 7.33) | 5.32 (t, 7.33) | 5.32 (t, 7.32) | 5.16 (t, 7.2) | 4.93 (m) | 5.37 (t, 7.2) |
| 4′ | 3.01 (s) | 3.01 (s) | 3.01 (s) | 3.02 (s) | 2.99 (br s) | 3.02 (s) |
| 6′ | 6.09 (s) | 6.09 (s) | 6.09 (s) | 6.31 (s) | 6.08 (s) | 6.15 (s) |
| 8′ | 1.84 (s) | 1.84 (s) | 1.84 (s) | 1.82 (s) | 1.83 (d, 1.22) | 1.83 (s) |
| 3′‐CH3 | 1.78 (s) | 1.78 (s) | 1.78 (s) | 1.91 (s) | 1.76 (d, 1.31) | 1.78 (s) |
| 7′‐CH3 | 2.12 (s) | 2.12 (s) | 2.12 (s) | 2.16 (s) | 2.11 (d, 1.22) | 2.16 (s) |
| Fatty acid | ||||||
| 1″ | — | — | 2.78 (dd, 6.60, 5.87) | — | — | — |
| 2″ | 2.33 (dd, 7.70, 7.32) | 2.33 (dd, 7.70, 7.32) | 2.33 (dd, 7.69, 7.33) | 2.35 (t, 7.6) | — | 2.35 (t, 7.6) |
| 3″ | 1.61 (m) | 1.61 (m) | 1.62 (m) | — | — | — |
| 4″ | — | — | — | — | — | — |
| 5″ | — | — | — | — | — | — |
| 6″ | — | — | — | — | — | — |
| 7″ | 1.25 (m) | 1.25 (m) | 1.62 (m) | — | — | — |
| 8″ | 2.04 (m) | — | — | — | ||
| 9″ | 5.34 (m) | — | — | 5.34 (m) | ||
| 10″ | 5.34 (m) | — | — | 5.34 (m) | ||
| 11″ | — | — | — | |||
| 12″ | 5.34 (m) | — | — | — | ||
| 13″ | 5.34 (m) | — | — | — | ||
| 14″ | 2.04 (m) | — | — | — | ||
| 15″ | 1.62 (m) | — | — | — | ||
| Others | — | — | 1.27 (m) | — | — | — |
| Terminal CH3 | 0.88 (t, 6.96) | 0.88 (t, 6.96) | 0.86 (t, 6.96) | 0.86 (t, 6.8) | — | 0.86 (t, 6.8) |
| 3‐OH | 12.38 (s) | 12.38 (s) | 12.38 (s) | — | 12.39 (s) | — |
| 5‐OCH3 | 3.91 (s) | 3.91 (s) | 3.91 (s) | 3.91 (s) | 3.90 (s) | 3.91 (s) |
| Solvent | CDCl3 | |||||
| Reference | [9] | [20] | [31] | [1] | ||
TABLE 3.
13C NMR data of hericenones C–E (3–5), hericenone L (15) and [4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25).
| 13C NMR data | |||||
|---|---|---|---|---|---|
| Position | Hericenone C (3) | Hericenone D (4) | Hericenone E (5) | HericenoneL (15) | (25) |
| 1 | 138.68 | 138.70 | 138.71 | 138.1 | 138.7 |
| 2 | 112.88 | 112.91 | 112.89 | 107.8 | 112.9 |
| 3 | 162.92 | 162.94 | 162.91 | 162.3 | 162.9 |
| 4 | 117.29 | 117.33 | 117.28 | 117.3 | 117.3 |
| 5 | 163.47 | 163.49 | 163.48 | 163.2 | 163.5 |
| 6 | 105.55 | 105.55 | 105.56 | 105.6 | 105.6 |
| 7 | 62.90 | 62.90 | 62.89 | 62.9 | 62.9 |
| 8 | 193.11 | 193.10 | 193.10 | 169.7 | 193.1 |
| 1′ | 21.61 | 21.62 | 21.62 | 21.4 | 21.6 |
| 2′ | 126.25 | 126.27 | 126.26 | 126.3 | 126.3 |
| 3′ | 130.34 | 130.35 | 130.23 | 130.2 | 130.2 |
| 4′ | 55.56 | 55.55 | 55.64 | 55.6 | 55.6 |
| 5′ | 199.53 | 199.54 | 199.47 | 199.5 | 199.6 |
| 6′ | 122.81 | 122.85 | 122.84 | 122.3 | 122.3 |
| 7′ | 155.45 | 155.42 | 155.38 | 155.2 | 155.4 |
| 8′ | 27.67 | 22.66 | 27.65 | 27.5 | 27.5 |
| 3′‐CH3 | 16.40 | 16.41 | 16.40 | 16.2 | 16.4 |
| 7′‐CH3 | 20.67 | 20.67 | 20.65 | 20.6 | 20.6 |
| Fatty acid | |||||
| 1″ | 173.19 | 173.20 | 173.10 | 172.9 | 173.1 |
| 2″ | 34.23 | 34.25 | 34.22 | 34.3 | 34.2 |
| 3″ | 31.93, 29.70, 29.68, 29.66, 29.65, 29.44, 29.36, 29.23, 29.12, 24.88, 22.70 |
24.89 29.13–31.94 |
22.59 22.70 24.85 25.64 27.17 27.21 29.08 29.13 29.35 29.57 31.53 127.91 128.09 129.99 130.21 |
— | — |
| 4″ | — | — | |||
| 5″ | — | — | |||
| 6″ | — | — | |||
| 7″ | — | — | |||
| 8″ | — | — | |||
| 9″ | — | 129.7, 130.0 | |||
| 10″ | — | ||||
| 11″ | — | — | |||
| 12″ | — | — | |||
| 13″ | — | — | |||
| 14″ | — | — | |||
| 15″ | — | — | |||
| Others | — | — | |||
| Terminal CH3 | 14.32 | 14.12 | 14.08 | 14.1 | 14.1 |
| 5‐OCH3 | 55.93 | 55.93 | 55.93 | 55.9 | 55.9 |
| Solvent | CDCl3 | ||||
| Reference | [9] | [25] | [9] | [20] | [1] |
Hericenone L (15), a palmitic ester derivative of hericenone, was reported by Ma et al. [20]. 1H NMR of hericenone L was quite similar to that of hericenone C, except for the absence of a formyl proton signal (δ 10.11 in hericenone C) (3). In addition, the 13C NMR spectrum of hericenone L was also similar to that of hericenone C. The difference between hericenone L and hericenone C is the C‐8 chemical shift (169.7 in hericenone L vs. 193.11 in hericenone C). It is speculated that the formyl group in hericenone C has been oxidated into the carboxylic group in hericenone L. Its 1H NMR and 13C NMR are shown in Tables 2 and 3.
Tamrakar et al. reported the deacetylation of hericenone C (3) to yield deacylhericenone (18) [31]. Structural analysis confirmed that this modification simplified the molecule while preserving its core aromatic and terpenoid features. LC–QTOF–MS and 1H NMR analyses characterized the deacetylated product, deacylhericenone (18). The absence of aliphatic proton signals corresponding to the palmitoyl chain further corroborated the successful removal of the acyl group. Its 1H NMR data is shown in Table 2.
[4‐[(2E)‐3,7‐dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25) was isolated by Ma et al. [1], where it was erroneously assigned the name hericenone I. However, this nomenclature appears to be incorrect, as the name hericenone I had already been used in a prior publication by Ueda et al. [17] to describe a structurally distinct compound (5‐methoxy‐2‐methyl‐2‐(4‐methyl‐2‐oxopent‐3‐enyl)‐3,4‐dydro‐2H‐furo[3,4‐h]chromen‐7(9H)‐one). The misassignment likely arose from an oversight in cross‐referencing the earlier work. To avoid confusion, we have retained the systematic IUPAC name for compound 25 as reported in the 2012 study [20]. Its 1H NMR and 13C NMR spectral data are shown in Tables 2 and 3.
The NMR features of hericenones F (6), G (7), and H (8), reveal structurally related chromanyl methyl esters with distinct fatty acid components. All three compounds share a chromanyl core featuring a formyl group, a methoxy substitution, and a methylated side chain. Fatty acid esters distinguish the compounds: hericenone F (6) contains a palmitate (16:0) chain, hericenone G (7) has a stearate (18:0) chain, hericenone H (8) features a linoleate (18:2Δ9,12) ester, marked by olefinic protons (δ 5.34, m) and allylic shifts (δ 2.77, dd, J = 6.61, 6.60 Hz). Methanolysis yields methyl palmitate/stearate/linoleate, validating ester linkages. All compounds are racemic, a result of biosynthetic cyclization at the C‐3′ position, as confirmed by CD spectroscopy. The full NMR data are shown in Tables 4 and 5 [24].
TABLE 4.
1H NMR data of hericenones F (6), G (7), H (8), and R (24).
| 1H NMR data (multiplicity, J in Hz) | ||||
|---|---|---|---|---|
| Position | Hericenone F (6) | Hericenone G (7) | Hericenone H (8) | Hericenone R (24) |
| 3 |
2.01 (ddd, 13.94, 6.61, 6.61) 1.91 (ddd, 13.94, 6.60, 6.60) |
2.00 (ddd, 13.92, 6.60, 6.60) 1.90 (ddd, 13.92, 6.96, 6.96) |
2.01 (m) 1.92 (ddd, 13.94, 7.34, 7.34) |
2.01 (m) 1.91 (dt, 13.6, 6.9) |
| 4 | 2.64 (dd, 6.61, 6.60) | 2.63 (dd, 6.96, 6.60) | 2.63 (dd, 7.34, 6.60) | 2.63 (t, 6.8) |
| 6 | 6.55 (s) | 6.54 (s) | 6.54 (s) | 6.54 (s) |
| 1′ |
2.82 (d, 13.94) 2.66 (d, 13.94) |
2.82 (d, 14.29) 2.66 (d, 14.29) |
2.82 (d, 13.94) 2.66 (d, 13.94) |
2.82 (d, 14.2) 2.66 (d, 14.2) |
| 3′ | 6.06 (s) | 6.06 (s) | 6.06 (s) | 6.06 (sept, 1.2) |
| 4′‐CH3 | 2.14 (s) | 2.14 (s) | 2.15 (s) | 2.14 (d, 1.2) |
| 5′ | 1.86 (s) | 1.86 (s) | 1.86 (s) | 1.86 (d, 1.2) |
| 2‐CH3 | 1.44 (s) | 1.44 (s) | 1.44 (s) | 1.44 (s) |
| 7‐CH2 | 5.51 (s) | 5.51 (s) | 5.51 (s) | 5.51 (s) |
| Fatty acid | ||||
| 2″ | 2.41 (t, 7.33) | 2.41 (t, 7.33) | 2.41 (t, 7.33) | 2.41 (t, 7.6) |
| 3″ | 1.69 (m) | 1.69 (m) | 1.69 (m) | 1.69 (m) |
| 4″ | — | — | — | — |
| 5″ | — | — | — | — |
| 6″ | — | — | — | — |
| 7″ | 1.25 (m) | 1.25 (m) | 1.69 (m) | — |
| 8″ | 2.03 (m) | 2.00 (m) | ||
| 9″ | 5.34 (m) | 5.34 (m) | ||
| 10″ | 5.34 (m) | 5.34 (m) | ||
| 11″ | 2.77 (dd, 6.61, 6.60) | 2.00 (m) | ||
| 12″ | 5.34 (m) | 1.28 (m) | ||
| 13″ | 5.34 (m) | |||
| 14″ | 2.03 (m) | |||
| 15″ | 1.69 (m) | |||
| Others | — | |||
| Terminal CH3 | 0.88 (t, 6.60) | 0.88 (t, 6.59) | 0.88 (t, 6.60) | 0.87 (t, 0.68) |
| 2‐CHO | 10.41 (s) | 10.41 (s) | 10.42 (s) | 10.41 (s) |
| 5‐OCH3 | 3.88 (s) | 3.88 (s) | 3.88 (s) | 3.88 (s) |
| Solvent | CDCl3 | |||
| Reference | [24] | [18] | ||
TABLE 5.
13C NMR data of hericenones F (6), G (7), H (8), and R (24).
| 13C NMR data | ||||
|---|---|---|---|---|
| Position | Hericenone F (6) | Hericenone G (7) | Hericenone H (8) | Hericenone R (24) |
| 2 | 76.9 | 76.9 | 76.7 | 77.0 |
| 3 | 30.1 | 30.1 | 30.0 | 30.1 |
| 4 | 16.5 | 16.5 | 16.4 | 16.6 |
| 4a | 109.2 | 109.2 | 109.2 | 109.4 |
| 5 | 161.9 | 161.9 | 161.9 | 162.1 |
| 6 | 100.8 | 100.8 | 100.8 | 100.9 |
| 7 | 139.7 | 139.7 | 139.6 | 139.8 |
| 8 | 115.8 | 115.8 | 115.8 | 115.9 |
| 8a | 158.3 | 158.3 | 158.3 | 158.4 |
| 1′ | 52.5 | 52.5 | 52.5 | 52.6 |
| 2′ | 197.9 | 197.9 | 197.9 | 198.1 |
| 3′ | 125.0 | 125.0 | 124.9 | 125.1 |
| 4′ | 156.4 | 156.4 | 156.4 | 156.6 |
| 4′‐CH3 | 20.8 | 20.8 | 20.8 | 21.0 |
| 5′ | 27.8 | 27.8 | 27.8 | 27.9 |
| 2‐CH3 | 24.5 | 24.5 | 24.5 | 24.6 |
| 7‐CH2 | 64.5 | 64.5 | 64.6 | 64.7 |
| Fatty acid | ||||
| 1″ | 173.3 | 173.3 | 173.2 | 173.4 |
| 2″ | 34.5 | 34.4 | 34.4 | 34.6 |
| 3″ | 25.1 | 25.1 | 25.1 | 25.2 |
| 4″ |
31.9 29.7 29.7 29.6 29.5 29.4 29.3 29.3 22.7 |
31.9 29.7 29.7 29.7 29.6 29.5 29.4 29.3 29.3 22.7 |
31.5 29.6 29.3 29.2 29.1 27.2 25.6 22.6 127.9 128.1 130.0 130.2 |
22.8 27.31 27.36 29.25 29.35 29.36 29.46 29.47 29.66 29.84 29.90 32.0 129.9 130.2 |
| 5″ | ||||
| 6″ | ||||
| 7″ | ||||
| 8″ | ||||
| 9″ | ||||
| 10″ | ||||
| 11″ | ||||
| 12″ | ||||
| 13″ | ||||
| 14″ | ||||
| 15″ | ||||
| Others | ||||
| Terminal CH3 | 14.1 | 14.1 | 14.1 | 14.3 |
| 2‐CHO | 190.4 | 190.3 | 190.3 | 190.5 |
| 5‐OCH3 | 55.6 | 55.6 | 55.6 | 55.7 |
| Solvent | CDCl3 | |||
| Reference | [24] | [18] | ||
Hericenone R (24) shares the same core skeleton as previously reported analogues but differs in its fatty acid side chain. According to a recent study by Ruan et al. [18], hericenone R (24) features an oleate chain (18:1Δ9). The NMR data supporting its structural elucidation are summarized in Tables 4 and 5.
As previously mentioned in this review, 3‐hydroxyhericenone F (9a) was first reported by Ueda et al. [17] as (2S,3S)‐8‐formyl‐3‐hydroxy‐5‐methoxy‐2‐methyl‐2‐(4‐methyl‐2‐oxopent‐3‐enyl)chroman‐7‐ylmethyl palmitate. However, in 2021, Kobayashi et al. [3] revised its structure through detailed cyclization mode analysis and NMR spectroscopic studies. The revised compound, named hericenone Z (9b), was assigned as (±)‐((S*)‐7‐formyl‐2‐((R*)‐2‐hydroxy‐6‐methyl‐4‐oxohept‐5‐en‐2‐yl)‐4‐methoxy‐2,3‐dihydrobenzofuran‐6‐yl)methyl palmitate, with the following NMR data: 1H NMR (400 MHz, CDCl3) δ 10.24 (1H, br s), 6.51 (1H, br s), 6.06 (1H, m), 5.48 (2H, br s), 4.93 (1H, dd, J = 9.6, 7.5 Hz), 4.68 (1H, s, OH), 3.89 (3H, s), 3.18 (1H, dd, J = 16, 7.2 Hz), 3.12 (1H, dd, J = 16, 9.6 Hz), 2.87 (1H, d, J = 17 Hz), 2.65 (1H, d, J = 17 Hz), 2.39 (2H, t, J = 7.5 Hz), 2.18 (3H, br s), 1.91 (3H, br s), 1.67 (2H, quint, J = 7.4 Hz), 1.33–1.23 (24H, m), 1.18 (3H, s), 0.88 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 202.0, 187.8, 173.4, 166.0, 160.5, 159.1, 140.4, 124.5, 114.1, 111.5, 103.7, 89.3, 73.5, 64.4, 55.8, 49.3, 34.5, 32.1, 29.83, 29.79, 29.74, 29.61, 29.49, 29.44, 29.35, 28.1, 27.1, 25.2, 22.8, 21.7, 21.3, 14.3 [3]. For readers' reference, we have provided both structures; the originally proposed one (9a) and the corrected one (9b) to highlight the key differences.
The NMR features of hericenones I (10) and J (11), reveal distinct structural frameworks. Hericenone I (10) exhibits a chroman skeleton and a γ‐lactone moiety. Hericenone J (11) features a benzolactone ring system. 13C NMR highlights carbonyls at δ 171.8 (C‐7, lactone in 10) and δ 172.8 (C‐1, benzolactone in 11), with downfield shifts for olefinic and lactone carbons. CD spectra indicated racemic mixtures for both compounds, likely due to biosynthetic cyclization. The NMR analyses defined hericenone I (10) as 5‐methoxy‐2‐methyl‐2‐(4‐methyl‐2‐oxopent‐3‐enyl)‐3,4‐dihydro‐2H‐furo[3,4‐h]chromen‐7(9H)‐one and hericenone J (11) as (E)‐6‐(3,7‐dimethylocta‐2,6‐dienyl)‐7‐hydroxy‐5‐methoxyisobenzofuran‐1(3H)‐one [17].
Isohericenone J (12), a new isobenzofuranone derivative, reported by Li et al. [19], is a structural isomer of hericenone J (11), sharing the same molecular formula (C19H24O4) but differing in their atomic arrangement.
The NMR spectral data of hericenones I (10), J (11), and isohericenone J (12) are shown in Table 6.
TABLE 6.
NMR data of hericenones I (10), J (11), and isohericenone J (12).
| 1H NMR data (multiplicity, J in Hz) | 13C NMR data | |||||
|---|---|---|---|---|---|---|
| Position | Hericenone I (10) | Hericenone J (11) | Isohericenone J (12) | Hericenone I (10) | Hericenone J (11) | Isohericenone J (12) |
| 1 | — | — | — | — | 172.8 | 172.2 |
| 2 | — | — | — | 76.5 | — | — |
| 3 |
1.94 (m) 2.04 (m) |
5.21 (s) | 5.21 (s) | 30.3 | 70.3 | 68.3 |
| 3a | — | — | — | — | 145.9 | 127.3 |
| 4 | 2.70 (m) | 6.46 (s) | — | 17.6 | 96.0 | 150.3 |
| 4a | — | — | — | 116.8 | — | — |
| 5 | — | — | — | 159.3 | 164.8 | 121.7 |
| 6 | 6.88 (s) | — | — | 97.0 | 117.0 | 159.3 |
| 6a | — | — | — | 125.1 | — | — |
| 7 | — | — | 6.93 (s) | 171.8 | 154.5 | 98.5 |
| 7a | — | — | — | 104.3 | 124.9 | |
| 9 |
5.11 (d, 15.1) 5.15 (d, 15.1) |
— | — | 68.0 | — | — |
| 9a | — | — | — | 128.0 | — | — |
| 10 | — | — | — | 148.5 | — | — |
| 2‐CH3 | 1.41 (s) | — | — | 24.7 | — | — |
| OCH3 | 3.87 (s) | 3.88 (s) | 3.84 (s) | 56.0 | 56.1 | 56.2 |
| 1′ |
2.65 (d, 14.4) 2.76 (d, 14.4) |
3.34 (d, 7.0) | 3.49 (d, 7.5) | 52.3 | 21.6 | 23.0 |
| 2′ | — | 5.16 (t, 7.0) | 5.21 (t, 7.5) | 197.7 | 121.3 | 120.5 |
| 3′ | 6.05 (s) | 125.0 | 135.8 | 140.2 | ||
| 4′ | — | 1.94 (t, 7.6) | 2.07 (m) a | 156.2 | 39.7 | 39.7 |
| 5′ | 1.87 (s) | 2.03 (m) | 2.08 (m) a | 27.9 | 26.7 | 26.3 |
| 6′ | — | 5.04 (t, 6.7) | 5.00 (t, 7.5) | — | 124.3 | 123.6 |
| 7′ | — | — | — | — | 131.2 | 132.4 |
| 8′ | — | 1.62 (s) | 1.63 (s) | — | 25.6 | 25.7 |
| 3′‐CH3 | — | 1.75 (s) | 1.79 (s) | — | 16.1 | 16.3 |
| 4′‐CH3 | 2.14 (s) | — | — | 20.9 | — | — |
| 7′‐CH3 | — | 1.55 (s) | 1.56 (s) | — | 17.6 | 17.8 |
| Solvent | CDCl3 | CDCl3 | CDCl3 | CDCl3 | CDCl3 | CDCl3 |
| Reference | [17] | [19] | [17] | [19] | ||
Overlapped.
Hericenone K (13) and 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) shared similar NMR patterns but 14 is differed by an olefin instead of a saturated C‐3′–C‐4′ bond (δ 56.8 and 70.9, respectively) in 13 [8]. The NMR data of compounds 13 and 14 is shown in Table 7.
TABLE 7.
NMR data of hericenone K (13) and 3,4‐dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14).
| 1H NMR data (multiplicity, J in Hz) | 13C NMR data | |||
|---|---|---|---|---|
| Position | Hericenone K (13) | 3,4‐Dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) | Hericenone K (13) | 3,4‐Dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) |
| 2 | — | — | 78.0 | 76.8 |
| 3 |
1.93 (m) a 2.02 (m) a |
1.97 (m) | 31.0 | 30.0 |
| 4 |
2.63 (m) a 2.68 (m) a |
2.60 (dd, 17.6, 7.0), 2.66 (ddd,17.6, 6.2, 6.2) | 17.7 | 16.8 |
| 4a | — | — | 111.7 | 111.0 |
| 5 | — | — | 165.3 | 163.0 |
| 6 | 6.07 (s) | 6.42 (s) | 96.7 | 94.7 |
| 6a | — | — | 151.5 | 149.0 |
| 7 | 5.21 (m) | 5.14 (s) | 70.4 | 68.4 |
| 9 | — | — | 171.8 | b |
| 9a | — | — | 106.6 | 106.1 |
| 10 | — | — | 154.0 | b |
| 2‐CH3 | 1.39 (s) | 1.45 (s) | 24.0 | 24.0 |
| 5‐OCH3 | 3.93 (s) | 3.90 (s) | 56.8 | 56.0 |
| 1′ | 2.84 (d, 14.6), 2.93 (d, 14.6) | 2.76 (d, 14.3), 2.88 (d, 14.3) | 54.0 | 53.4 |
| 2′ | — | — | 211.3 | 198.5 |
| 3′ | 2.78 (d, 15.9), 2.89 (d, 15.9) | 6.41 (br s) | 56.8 | 125.1 |
| 4′ | — | — | 70.9 | 156.3 |
| 5′ | 1.25 (s) | 1.91 (d, 1.1) | 29.4 | 27.7 |
| 6′ | 1.23 (s) | 2.14 (d, 1.1) | 29.6 | 20.9 |
| Solvent | CD3OD | CDCl3 | CD3OD | CDCl3 |
| Reference | [8] | [45] | [8] | [45] |
4‐[3′,7′‐Dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methoxybenzyl alcohol (17) was first reported as a natural compound isolated from H. erinaceum in a study published by Miyazawa et al. 2012 [42]. However, before this, Arnone et al. [43] had already identified the same compound as a product of the methanolysis of hericenes A–C in their work. Its NMR data is shown in Table 8.
TABLE 8.
NMR data of 4‐[3′,7′‐Dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methoxybenzyl alcohol (17).
| Position | 1H NMR data (multiplicity, J in Hz) | 13C NMR data |
|---|---|---|
| 1 | — | 143.3 |
| 2 | — | 112.6 |
| 3 | — | 163.7 |
| 4 | — | 103.5 |
| 5 | — | 163.0 |
| 6 | 6.52 (s) | 103.5 |
| 7 | 4.94 (s) | 62.7 |
| 8 | 10.21 (s) | 193.6 |
| 1′ | 3.33 (d, 7.2) | 21.3 |
| 2′ | 5.17 (t, 7.2) | 121.5 |
| 3′ | — | 131.5 |
| 4′ | 1.95 (t, 7.6) | 39.8 |
| 5′ | 2.04 (m) | 26.7 |
| 6′ | 5.06 (br t, 6.8) | 124.4 |
| 7′ | — | 131.4 |
| 8′ | 1.64 (s) | 25.7 |
| 3′‐CH3 | 1.77 (s) | 16.0 |
| 7′‐CH3 | 1.57 (s) | 17.6 |
| 3‐OH | 12.37 (s) | — |
| 5‐OCH3 | 3.92 (s) | 55.8 |
| Solvent | CDCl3 | |
| Reference | [42] | |
5‐[(2E)‐3,7‐Dimethyl‐5‐carbonyl‐2,6‐octadiene‐1‐yl]‐2,3‐dihydro‐4‐hydroxy‐6‐methoxy‐2‐(2‐hydroxy)isoindole‐1‐one, named hericenone M (19) and 5‐[(2E)‐3,7‐dimethyl‐2,6‐octadiene‐1‐yl]‐2,3‐dihydro‐4‐hydroxy‐6‐methoxy‐2‐(2‐hydroxy)isoindole‐1‐one, named hericenone N (20), have been reported in a patent published in 2018 [23]. Their NMR data is shown in Table 9.
TABLE 9.
NMR data of hericenones M (19) and N (20).
| 1H NMR data (multiplicity, J in Hz) | 13C NMR data | |||
|---|---|---|---|---|
| Position | Hericenone M (19) | Hericenone N (20) | Hericenone M (19) | Hericenone N (20) |
| 1 | — | — | 168.1 | 168.2 |
| 3 | 4.39 (s) | 4.38 (s) | 49.3 | 49.2 |
| 3a | — | — | 121.6 | 131.9 |
| 4 | — | — | 150.3 | 150.3 |
| 5 | — | — | 119.7 | 120.3 |
| 6 | — | — | 158.8 | 158.8 |
| 7 | 6.76 (s) | 6.75 (s) | 96.8 | 96.4 |
| 7a | — | — | 132.1 | 122.8 |
| 1′ | 3.36 (s) | 3.31 (d, 7.0) | 23.0 | 22.8 |
| 2′ | 5.23 (dd, 6.5, 7.5) | 5.11 (t, 7.0) | 127.1 | 121.6 |
| 3′ | — | — | 129.8 | 134.5 |
| 4′ | 2.99 (s) | 1.89 (t, 8.0) | 56.3 | 39.8 |
| 5′ | — | 2.00 (t, 7.0) | 198.9 | 26.7 |
| 6′ | 6.09 (t, 1.5) | 5.02 (t, 7.0) | 123.4 | 124.6 |
| 7′ | — | — | 154.9 | 131.1 |
| 8′ | 1.81 (d, 1.0) | 1.59 (s) | 27.6 | 25.9 |
| 3′‐CH3 | 1.70 (s) | 1.73 (s) | 16.9 | 16.4 |
| 7′‐CH3 | 2.03 (d, 0.5) | 1.52 (s) | 20.6 | 17.9 |
| 1″ | 3.55 (d, 5.0) | 3.54 (d, 5.0) | 45.2 | 45.2 |
| 2″ | 3.60 (d, 5.0) | 3.59 (d, 5.0) | 59.9 | 49.9 |
| 6‐OCH3 | 3.80 (s) | 3.80 (s) | 55.0 | 56.3 |
| 4‐OH | 9.53 (br) | 9.46 (br s) | — | — |
| 2″‐OH | 4.85 (t, 5.0) | 4.85 (t, 5.5) | — | — |
| Solvent | DMSO‐d6 | |||
| Reference | [23] | |||
The NMR features of hericenones O (21), P (22), and Q (23), reported by Ruan et al. [18], reveal structurally related benzaldehyde derivatives with distinct fatty acid ester components. Hericenone O (21) contains linoleate ester chain is evident from olefinic protons at δ 5.32–5.36. Hericenone P (22) shares a similar benzaldehyde core but contains a palmitate ester. Hericenone Q (23) shares a similar benzaldehyde core but contains a stearate ester. Key structural distinctions between the three compounds arise from the ester‐linked fatty acid: O (21) (linoleate), P (22) (palmitate), and Q (23) (stearate), confirmed by methanolysis and GC/MS. These NMR analyses, combined with HR–ESI–MS and IR data, define hericenones O–Q (21–23) as 4‐((E)‐3′,7′‐dimethyl‐5′‐oxo‐2′,6′‐octadienyl)‐2‐formyl‐3‐hydroxy‐5‐methoxybenzyl esters with variable fatty acid chains. Their NMR data is shown in Table 10.
TABLE 10.
NMR data of hericenones O–Q (21–23).
| 1H NMR data (multiplicity, J in Hz) | 13C NMR data | ||||
|---|---|---|---|---|---|
| Position | Hericenone O (21) | Hericenone P (22) | Hericenone Q (23) | Hericenone O (21) | Hericenone P (22) |
| 1 | — | — | — | 138.9 | 138.9 |
| 2 | — | — | — | 112.9 | 112.9 |
| 3 | — | — | — | 163.1 | 163.1 |
| 4 | — | — | — | 117.6 | 117.6 |
| 5 | — | — | — | 163.1 | 163.1 |
| 6 | 6.51 (s) | 6.52 (s) | 6.52 (s) | 105.6 | 105.6 |
| 7 | 5.32 (s) | 5.32 (s) | 5.32 (s) | 63.1 | 63.1 |
| 8 | 10.11 (s) | 10.11 (s) | 10.11 (s) | 193.3 | 193.3 |
| 1′ | 2.81 (m) | 2.81 (m) | 2.81 (m) | 20.8 | 20.8 |
| 2′ | — | 2.28 (m) | — | 39.9 | 39.9 |
| 3′ | — | — | — | 163.7 | 163.7 |
| 4′ | 6.01 (m) | 6.01 (m) | — | 126.5 | 126.5 |
| 5′ | — | — | — | 191.9 | 191.9 |
| 6′ | 6.03 (m) | 6.04 (m) | 6.01 (m) | 125.7 | 125.7 |
| 7′ | — | — | — | 154.3 | 154.3 |
| 8′ | 1.87 (d, 1.24) | 1.88 (d, 1.24) | 1.88 (d, 1.24) | 27.8 | 27.9 |
| 3′‐CH3 | 2.15 (d, 1.24) | 2.15 (d, 1.24) | 2.15 (d, 1.24) | 19.4 | 19.4 |
| 7′‐CH3 | 2.23 (d, 1.24) | 2.23 (d, 1.24) | 2.23 (d, 1.24) | 20.7 | 20.7 |
| Fatty acid | |||||
| 1″ | — | — | — | 173.3 | 173.4 |
| 2″ | 2.34 (t, 7.6) | 2.34 (t, 7.6) | 2.34 (t, 7.6) | 34.3 | 34.4 |
| 3″ | 1.62 (m) | 1.61 (m) | 1.61 (m) | — | 32.1, 29.83, 29.82, 29.81, 29.80, 29.78, 29.72, 29.59, 29.51, 29.37, 29.25, 25.0, 22.8 |
| 4″ | 1.27 (m) | 1.25 (m) | 1.25 (m) | — | |
| 5″ | — | ||||
| 6″ | — | ||||
| 7″ | 1.62 (m) | 1.61 (m) | — | ||
| 8″ | 2.04 (m) | — | |||
| 9″ | 5.36 (dt, 8.6, 6.1) | — | 130.4 | ||
| 10″ | — | 130.2 | |||
| 11″ | 2.78 (dd, 6.6, 5.9) | — | — | ||
| 12″ | 5.32 (dt, 8.0, 6.5) | — | 128.2 | ||
| 13″ | — | 128.0 | |||
| 14″ | 2.04 (m) | — | — | ||
| 15″ | 1.62 (m) | 1.61 (m) | 25.8 | ||
| 16″ | — | 0.88 (t, 6.8) | — | 25.0 | 14.3 |
| 17″ | — | — | — | 22.7 | — |
| 18″ | 0.88 (t, 6.8) | — | 0.87 (t, 6.8) | 14.2 | — |
| Others | — | — | 2.28 (m) | 31.7, 29.70, 29.48, 29.26, 29.22, 29.21, 27.33, 27.31, 25.8, 25.0, 22.7 (C3″‐8″, 11″, 14″‐17″) | — |
| 3‐OH | 12.39 (s) | 12.39 (s) | 12.39 (s) | — | — |
| 5‐OCH3 | 3.90 (s) | 3.90 (s) | 3.90 (s) | 56.1 | 56.1 |
| Solvent | CDCl3 | ||||
| Reference | [18] | ||||
7. Molecular Formula and Exact Mass in Hericenones Characterization
The molecular formula and calculated exact mass of hericenones are critical for their structural identification, dereplication, and mass spectrometry‐based detection. Since these fungal metabolites often exhibit close structural similarities, precise mass measurements help distinguish between isomers and confirm proposed structures. High‐resolution mass spectrometry (HRMS) relies on exact masses to assign elemental compositions, ensuring accurate characterization. In addition, the molecular formula provides insights into biosynthetic pathways and functional group modifications. Below (Table 11) is a compilation of key hericenones, their molecular formulas, and calculated exact masses for reference.
TABLE 11.
Molecular formula and calculated exact mass of covered compounds in this review.
| Compound | Molecular formula | Calculated exact mass (Da) |
|---|---|---|
| Hericenone A (1) | C19H22O5 | 330.1467 |
| Hericenone B (2) | C27H31NO4 | 433.2253 |
| Hericenone C (3) | C35H54O6 | 570.3920 |
| Hericenone D (4) | C37H58O6 | 598.4233 |
| Hericenone E (5) | C37H54O6 | 594.3920 |
| Hericenone F (6) | C35H54O6 | 570.3920 |
| Hericenone G (7) | C37H58O6 | 598.4233 |
| Hericenone H (8) | C37H54O6 | 594.3920 |
| Hericenone Z (9b) | C35H54O7 | 586.3870 |
| Hericenone I (10) | C19H22O5 | 330.1467 |
| Hericenone J (11) | C19H24O4 | 316.1675 |
| Isohericenone J (12) | C19H24O4 | 316.1675 |
| Hericenone K (13) | C19H24O6 | 348.1573 |
| 3,4‐Dihydro‐5‐methoxy‐2‐methyl‐2‐(4′‐methyl‐2′‐oxo‐3′‐pentenyl)‐9(7H)‐oxo‐2H‐furo[3,4‐h]benzopyran (14) | C19H22O5 | 330.3800 |
| Hericenone L (15) | C35H54O7 | 586.3870 |
| Isohericenone (16) | C27H31NO4 | 433.2253 |
| 4‐[3′,7′‐Dimethyl‐2′,6′‐octadienyl]‐2‐formyl‐3‐hydroxy‐5‐methyoxybenzylalcohol (17) | C19H26O4 | 318.1831 |
| Deacylhericenone (18) | C19H24O5 | 332.1624 |
| Hericenone M (19) | C21H27NO5 | 373.1889 |
| Hericenone N (20) | C21H29NO4 | 359.2097 |
| Hericenone O (21) | C37H54O6 | 594.3920 |
| Hericenone P (22) | C35H54O6 | 570.3920 |
| Hericenone Q (23) | C37H58O6 | 598.4233 |
| Hericenone R (24) | C37H56O6 | 596.4077 |
| [4‐[(2E)‐3,7‐Dimethyl‐5‐oxo‐2,6‐octadien‐1‐yl]‐2‐formyl‐3‐hydroxy‐5‐methoxyphenyl]methyl (9Z)‐9‐octadecenoate (25) | C37H56O6 | 596.4077 |
8. Conclusion
This comprehensive review highlights the remarkable pharmacological potential of hericenones, a distinctive class of geranylated resorcinols from the medicinal mushroom H. erinaceus, by systematically examining their bioactivities, isolation methods, and NMR spectroscopic characteristics to provide a valuable resource for future research. The detailed discussion underscores their significant therapeutic potential, including neuroprotective effects, particularly through NGF stimulation and neurite outgrowth enhancement, making them promising candidates for managing neurodegenerative diseases, as well as their anti‐inflammatory, antioxidant, anticancer, antiplatelet, and antidiabetic properties, which collectively broaden their potential applications. Furthermore, the review offers practical guidance for natural product chemists by detailing isolation methodologies and structural elucidation, with structural insights from NMR studies and the reviewed isolation strategies poised to facilitate future research efforts. In summary, hericenones represent a bridge between traditional medicine and modern drug discovery, and their multifaceted bioactivities, coupled with their natural origin, highlighting them as attractive molecules for developing novel neuroprotective agents, functional foods, and therapies for metabolic and inflammatory disorders. However, challenges remain in optimizing their bioavailability, scaling up production, and elucidating the exact molecular mechanisms, and addressing these limitations through interdisciplinary research will be crucial for unlocking their full potential in global health, particularly for aging populations facing neurodegenerative and chronic diseases.
Conflicts of Interest
The authors declare no conflicts of interest.
Contributor Information
Ahmed Othman, Email: ah.othman@azhar.edu.eg.
Kuniyoshi Shimizu, Email: shimizu.kuniyoshi.381@m.kyushu-u.ac.jp.
Data Availability Statement
The authors have nothing to report.
References
- 1. Ma B. J., Yu H. Y., Shen J. W., et al., “Cytotoxic Aromatic Compounds From Hericium erinaceum ,” Journal of Antibiotics 63 (2010): 713–715, 10.1038/ja.2010.112. [DOI] [PubMed] [Google Scholar]
- 2. Wang J., Wu J., Yamaguchi R., et al., “Uncovering Hericenones From the Fruiting Bodies of Hericium erinaceus Through Interdisciplinary Collaboration,” Journal of Natural Products 88 (2025): 80–85, 10.1021/acs.jnatprod.4c01018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kobayashi S., Tamura T., Koshishiba M., et al., “Total Synthesis, Structure Revision, and Neuroprotective Effect of Hericenones C‐H and Their Derivatives,” Journal of Organic Chemistry 86 (2021): 2602–2620, 10.1021/ACS.JOC.0C02681. [DOI] [PubMed] [Google Scholar]
- 4. Jianzhao Q., Jing W., Shijie K., et al., “The Chemical Structures, Biosynthesis, and Biological Activities of Secondary Metabolites From the Culinary‐Medicinal Mushrooms of the Genus Hericium: A Review,” Chinese Journal of Natural Medicines 22 (2024): 676–698, 10.1016/S1875-5364(24)60590-X. [DOI] [PubMed] [Google Scholar]
- 5. Kawagishi H., Ando M., and Mizuno T., “Hericenone A and B as Cytotoxic Principles From the Mushroom Hericium erinaceum ,” Tetrahedron Letters 31 (1990): 373–376, 10.1016/S0040-4039(00)94558-1. [DOI] [Google Scholar]
- 6. Mori K., Obara Y., Hirota M., et al., “Nerve Growth Factor‐Inducing Activity of Hericium erinaceus in 1321N1 Human Astrocytoma Cells,” Biological and Pharmaceutical Bulletin 31 (2008): 1727–1732, 10.1248/BPB.31.1727. [DOI] [PubMed] [Google Scholar]
- 7. Saitsu Y., Nishide A., Kikushima K., Shimizu K., and Ohnuki K., “Improvement of Cognitive Functions by Oral Intake of Hericium erinaceus ,” Biomedical Research 40 (2019): 125–131. [DOI] [PubMed] [Google Scholar]
- 8. Zhang C. C., Yin X., Cao C. Y., Wei J., Zhang Q., and Gao J. M., “Chemical Constituents From Hericium erinaceus and Their Ability to Stimulate NGF‐mediated Neurite Outgrowth on PC12 Cells,” Bioorganic and Medicinal Chemistry Letters 25 (2015): 5078–5082, 10.1016/j.bmcl.2015.10.016. [DOI] [PubMed] [Google Scholar]
- 9. Kawagishi H., Ando M., Sakamoto H., et al., “Hericenones C, D and E, Stimulators of Nerve Growth Factor (NGF)‐Synthesis, From the Mushroom Hericium erinaceum ,” Tetrahedron Letters 32 (1991): 4561–4564, 10.1016/0040-4039(91)80039-9. [DOI] [Google Scholar]
- 10. Xie G., Tang L., Xie Y., and Xie L., “Secondary Metabolites From Hericium erinaceus and Their Anti‐Inflammatory Activities,” Molecules 27 (2022): 2157, 10.3390/MOLECULES27072157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kobayashi S., “Total Synthesis of Geranyl‐Resorcinols Isolated From Mushrooms of Genus Hericium ,” Synthesis 55 (2023): 417–432, 10.1055/A-1944-9623. [DOI] [Google Scholar]
- 12. Iacovelli R., Poon F., and Haslinger K., “Identification and Reconstitution of the First Two Enzymatic Steps for the Biosynthesis of Bioactive Meroterpenoids From Hericium Erinaceus (Lion's Mane Mushroom),” Molecules 29 (2024): 5576, 10.3390/MOLECULES29235576/S1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Wang X. L., Xu K. P., Long H. P., et al., “New Isoindolinones From the Fruiting Bodies of Hericium erinaceum ,” Fitoterapia 111 (2016): 58–65, 10.1016/J.FITOTE.2016.04.010. [DOI] [PubMed] [Google Scholar]
- 14. Ashour A., Amen Y., Allam A. E., et al., “New Isoindolinones From the Fruiting Bodies of the Fungus Hericium erinaceus ,” Phytochemistry Letters 32 (2019): 10–14, 10.1016/J.PHYTOL.2019.04.017. [DOI] [Google Scholar]
- 15. Rama Rao A. V. and Reddy R. G., “First Unambiguous Total Synthesis of Hericenone A: Proposed Structure Revised,” Tetrahedron Letters 33 (1992): 4061–4064, 10.1016/0040-4039(92)88100-J. [DOI] [Google Scholar]
- 16. Kobayashi S., Tamanoi H., Hasegawa Y., Segawa Y., and Masuyama A., “Divergent Synthesis of Bioactive Resorcinols Isolated From the Fruiting Bodies of Hericium erinaceum: Total Syntheses of Hericenones A, B, and I, Hericenols B‐D, and Erinacerins A and B,” Journal of Organic Chemistry 79 (2014): 5227–5238, 10.1021/JO500795Z. [DOI] [PubMed] [Google Scholar]
- 17. Ueda K., Tsujimori M., Kodani S., et al., “An Endoplasmic Reticulum (ER) Stress‐Suppressive Compound and Its Analogues From the Mushroom Hericium erinaceum ,” Bioorganic & Medicinal Chemistry 16 (2008): 9467–9470, 10.1016/J.BMC.2008.09.044. [DOI] [PubMed] [Google Scholar]
- 18. Ruan Y., Han C., Wang D., et al., “New Benzaldehyde Derivatives From the Fruiting Bodies of Hericium erinaceus With Cytotoxic Activity,” Natural Product Research 37 (2023): 4089–4098, 10.1080/14786419.2023.2169687. [DOI] [PubMed] [Google Scholar]
- 19. Li W., Zhou W., Kim E. J., Shim S. H., Kang H. K., and Kim Y. H., “Isolation and Identification of Aromatic Compounds in Lion's Mane Mushroom and Their Anticancer Activities,” Food Chemistry 170 (2015): 336–342, 10.1016/J.FOODCHEM.2014.08.078. [DOI] [PubMed] [Google Scholar]
- 20. Ma B. J., Ma J. C., and Ruan Y., “Hericenone L, a New Aromatic Compound From the Fruiting Bodies of Hericium erinaceums ,” Chinese Journal of Natural Medicines 10 (2012): 363–365, 10.1016/S1875-5364(12)60072-7. [DOI] [Google Scholar]
- 21. Kim K. H., Noh H. J., Choi S. U., and Lee K. R., “Isohericenone, a New Cytotoxic Isoindolinone Alkaloid From Hericium erinaceum ,” Journal of Antibiotics 65 (2012): 575–577, 10.1038/ja.2012.65. [DOI] [PubMed] [Google Scholar]
- 22. Chen Z. G., Bishop K. S., Tanambell H., Buchanan P., Smith C., and Quek S. Y., “Characterization of the Bioactivities of an Ethanol Extract and Some of Its Constituents From the New Zealand Native Mushroom Hericium novae‐zealandiae ,” Food & Function 10 (2019): 6633–6643, 10.1039/C9FO01672D. [DOI] [PubMed] [Google Scholar]
- 23. Hunan Xinhui Pharmaceutical Co. Ltd ., Hericenone M and Hericenone N , CN 108440380 A (2018), https://patents.google.com/patent/CN108440380A/zh.
- 24. Kawagishi H., Ando M., Shinba K., et al., “Chromans, Hericenones F, G and H From the Mushroom Hericium erinaceum ,” Phytochemistry 32 (1992): 175–178, 10.1016/0031-9422(92)80127-Z. [DOI] [Google Scholar]
- 25. Huong L. M., Cuong X., and Thi Hong Ha T., “Chemical Constituents of the Fungus Hericium erinaceus SH1,” Journal of Chemistry 46 (2008): 96–101. [Google Scholar]
- 26. Corana F., Cesaroni V., Mannucci B., et al., “Array of Metabolites in Italian Hericium erinaceus Mycelium, Primordium, and Sporophore,” Molecules 24 (2019): 3511, 10.3390/MOLECULES24193511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Phan C. W., Lee G. S., Hong S. L., et al., “ Hericium erinaceus (Bull.: Fr) Pers. Cultivated Under Tropical Conditions: Isolation of Hericenones and Demonstration of NGF‐Mediated Neurite Outgrowth in PC12 Cells via MEK/ERK and PI3K‐Akt Signaling Pathways,” Food and Function 5 (2014): 3160–3169, 10.1039/C4FO00452C. [DOI] [PubMed] [Google Scholar]
- 28. Stamets P. E., Compositions and Methods for Enhancing Neuroregeneration and Cognition by Combining Mushroom Extracts Containing Active Ingredients Psilocin or Psilocybin With Erinacines or Hericenones Enhanced With Niacin , US 2018 /0021326 A1 (2018).
- 29. Ratto D., Corana F., Mannucci B., et al., “ Hericium Erinaceus Improves Recognition Memory and Induces Hippocampal and Cerebellar Neurogenesis in Frail Mice During Aging,” Nutrients 11 (2019): 715, 10.3390/NU11040715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Roda E., Priori E. C., Ratto D., et al., “Neuroprotective Metabolites of Hericium erinaceus Promote Neuro‐Healthy Aging,” International Journal of Molecular Sciences 22 (2021): 6379, 10.3390/IJMS22126379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Tamrakar S., Wang D., Hiraki E., et al., “Deacylated Derivative of Hericenone C Treated by Lipase Shows Enhanced Neuroprotective Properties Compared to Its Parent Compound,” Molecules 28 (2023): 4549, 10.3390/MOLECULES28114549/S1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Sutthibutpong T., Posansee K., Liangruksa M., et al., “Combining Deep Learning and Structural Modeling to Identify Potential Acetylcholinesterase Inhibitors From Hericium erinaceus ,” ACS Omega 9 (2024): 16311–16321, 10.1021/acsomega.3c10459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Noh H. J., Yoon J. Y., Kim G. S., et al., “Benzyl Alcohol Derivatives From the Mushroom Hericium erinaceum Attenuate LPS‐Stimulated Inflammatory Response Through the Regulation of NF‐κB and AP‐1 Activity,” Immunopharmacology and Immunotoxicology 36 (2014): 349–354, 10.3109/08923973.2014.947036. [DOI] [PubMed] [Google Scholar]
- 34. Lee D. G., Kang H. W., Park C. G., Ahn Y. S., and Shin Y., “Isolation and Identification of Phytochemicals and Biological Activities of Hericium ernaceus and Their Contents in Hericium Strains Using HPLC/UV Analysis,” Journal of Ethnopharmacology 184 (2016): 219–225, 10.1016/J.JEP.2016.02.038. [DOI] [PubMed] [Google Scholar]
- 35. Li J., Hamamura K., Yoshida Y., et al., “Hericenone C Attenuates the Second Phase of Formalin‐Induced Nociceptive Behavior by Suppressing the Accumulation of CD11c‐Positive Cells in the Paw Epidermis via Phosphorylated P65,” Biochemical and Biophysical Research Communications 720 (2024): 150077, 10.1016/J.BBRC.2024.150077. [DOI] [PubMed] [Google Scholar]
- 36. Tachabenjarong N., Rungsardthong V., Ruktanonchi U., et al., “Bioactive Compounds and Antioxidant activity of Lion's Mane Mushroom (Hericium erinaceus) From Different Growth Periods,” E3S Web of Conferences 355 (2022): 02016, 10.1051/e3sconf/202235502016. [DOI] [Google Scholar]
- 37. Mori K., Kikuchi H., Obara Y., et al., “Inhibitory Effect of Hericenone B From Hericium erinaceus on Collagen‐Induced Platelet Aggregation,” Phytomedicine 17 (2010): 1082–1085, 10.1016/J.PHYMED.2010.05.004. [DOI] [PubMed] [Google Scholar]
- 38. Hiraki E., Furuta S., Kuwahara R., et al., “Anti‐Obesity Activity of Yamabushitake (Hericium erinaceus) Powder in Ovariectomized Mice, and Its Potentially Active Compounds,” Journal of Natural Medicines 71 (2017): 482–491, 10.1007/S11418-017-1075-8. [DOI] [PubMed] [Google Scholar]
- 39. Lee S. K., Ryu S. H., Turk A., et al., “Characterization of α‐Glucosidase Inhibitory Constituents of the Fruiting Body of Lion's Mane Mushroom (Hericium erinaceus),” Journal of Ethnopharmacology 262 (2020): 113197, 10.1016/J.JEP.2020.113197. [DOI] [PubMed] [Google Scholar]
- 40. Zhang C., Li J., Hu C., et al., “Antihyperglycaemic and Organic Protective Effects on Pancreas, Liver and Kidney by Polysaccharides From Hericium erinaceus SG‐02 in Streptozotocin‐Induced Diabetic Mice,” Scientific Reports 7 (2017): 10847, 10.1038/S41598-017-11457-W. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Chen B., Han J., Bao L., Wang W., Ma K., and Liu H., “Identification and α‐Glucosidase Inhibitory Activity of Meroterpenoids From Hericium erinaceus ,” Planta Medica 86 (2020): 571–578, 10.1055/A-1146-8369. [DOI] [PubMed] [Google Scholar]
- 42. Miyazawa M., Takahashi T., Horibe I., and Ishikawa R., “Two New Aromatic Compounds and a New d‐Arabinitol Ester From the Mushroom Hericium erinaceum ,” Tetrahedron 68 (2012): 2007–2010, 10.1016/J.TET.2011.11.068. [DOI] [Google Scholar]
- 43. Arnone A., Cardillo R., Nasini G., and De Pava O. V., “Secondary Mold Metabolites: Part 46. Hericenes A‐C and Erinapyrone C, New Metabolites Produced by the Fungus Hericium erinaceus ,” Journal of Natural Products 57 (1994): 602–606, 10.1021/np50107a006. [DOI] [Google Scholar]
- 44. Noh H. J., Yang H. H., Kim G. S., et al., “Chemical Constituents of Hericium erinaceum Associated With the Inhibitory Activity Against Cellular Senescence in Human Umbilical Vascular Endothelial Cells,” Journal of Enzyme Inhibition and Medicinal Chemistry 30 (2015): 934–940, 10.3109/14756366.2014.995181. [DOI] [PubMed] [Google Scholar]
- 45. Yaoita Y. and Kikuchi M., “Constituents of Mushrooms. XXV. Structures of New Aromatic Compounds From the Fruiting Bodies of Hericium erinaceum (Bull.: Fr.) Pers,” Journal of Tohoku Pharmaceutical University 52 (2005): 39–42. [Google Scholar]
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Data Availability Statement
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