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Isolation and Bioactivity Evaluation of Terpenoids from the Medicinal Fungus Ganoderma sinense
Abstract
A new pentanorlanostane, ganosineniol A (1), eight new lanostane triterpenoids, ganosinoside A (2), ganoderic acid Jc (3), ganoderic acid Jd (4), ganodermatetraol (5), ganolucidic acid γa (6), ganolucidate F (7), ganoderiol J ( 8), and methyl lucidenate Ha ( 9), and a new sesquiterpenoid, ganosinensine (10), together with eleven known triterpenoids (11- 21), were isolated from the fruiting bodies of the fungus Ganoderma sinense. Chemical structures were determined based on spectroscopic evidence, including 1D, 2D NMR, and mass spectral data. Furthermore, all isolates were tested for cytotoxic activity and induction ability of hPXR-mediated CYP3A4 expression. Among them, ganoderic acid Jc (3) displayed selective inhibitory activity against HL-60 cells (IC₅₀ = 8.30 µM), and ganoderiol E (11) exhibited selective cytotoxic activity against MCF-7 cells (IC₅₀ = 6.35 µM). Meanwhile, compounds 5, 7, and ganolucidic acids B and C (19, 20) showed induction ability of hPXR-mediated CYP3A4 expression.
... Ganolucidic acid γa PXR-mediated CYP3A4 expression-NE G. sinense [198] 78. ...
... Ganolucidate F PXR-mediated CYP3A4 expression G. sinense [198] ...
... Ganoderic acid Jc Cytotoxicity against HL-60 cells (8.30 µM) G. sinense [198] ...
Mahesh C.A. Galappaththi, Nimesha M. Patabendige, Bhagya M.
Premarathne, Kalani K. Hapuarachchi, Saowaluck Tibpromma, Dong-Qin Dai,
Nakarin Suwannarach, Sylvie Rapior, Samantha C. Karunarathna.
A review of Ganoderma triterpenoids and their bioactivities.
Biomolecules, Special Issue Fungal Metabolism - Enzymes and Bioactive Compounds
II, 13 (1), 24 (2023). doi:10.3390/biom13010024. hal-03912698
___ For centuries, Ganoderma has been used as a traditional medicine in Asian countries to prevent and treat various diseases. Numerous publications are stating that Ganoderma species have a variety of beneficial medicinal properties, and investigations on different metabolic regulations of Ganoderma species, extracts or isolated compounds have been performed both in vitro and in vivo. However, it has frequently been questioned whether Ganoderma is simply a dietary supplement for health or just a useful "medication" for restorative purposes. More than 600 chemical compounds including alkaloids, meroterpenoids, nucleobases, nucleosides, polysaccharides, proteins, steroids and triterpenes were extracted and identified from Ganoderma, with triterpenes serving as the primary components. In recent years, Ganoderma triterpenes and other small molecular constituents have aroused the interest of chemists and pharmacologists. Meanwhile, considering the significance of the triterpene constituents in the development of new drugs, this review describes 495 compounds from 25 Ganoderma species published between 1984 and 2022, commenting on their source, biosynthetic pathway, identification, biological activities and biosynthesis, together with applications of advanced analytical techniques to the characterization of Ganoderma triterpenoids.
... Among the triterpenoids mentioned above, ganoderic acid Jc (51) has exhibited marked antitumour activity [38]. Significant anti-HIV-1 protease activity has been observed for ganoderic acid S1 (38) and ganodermic acid T-Q (48) [39]. ...
... Among the triterpenoids mentioned above, ganoderic acid Jc (51) has exhibited marked antitumour activity [38]. Significant anti-HIV-1 protease activity has been observed for ganoderic acid S1 (38) and ganodermic acid T-Q (48) [39]. Compounds ...
... subdivided into different groups according to different substituents and positions of double bonds. The C-8(9) double bonds are retained in compounds 57-78, while methyl lucidenate Ha (79) has a hydroxy substituent at C-29[38]. ...
Ganoderma lucidum is a multi-purpose plant medicine that is homologous to functional food. The most attractive properties of G. lucidum are its immunomodulatory and antitumour activities, which are mainly attributed to the following two major active components: G. lucidum polysaccharides and G. lucidum triterpenoids (GLTs). GLTs are effective as supplemental therapies and improve health when combined with other medications to treat hepatitis, fatigue syndrome, and prostate cancer. However, research investigating the mechanism and application of G. lucidum or GLTs in the treatment of diseases remains preliminary in terms of both the utilization efficacy and product type. This review offers comprehensive insight into the pharmacological activities of GLTs and their potential applications in the development of functional foods and nutraceuticals. Specifically, 83 GLTs were selected, and their molecular structures and chemical formulas were described. We also describe 7 ganoderic acids that are currently at different stages of clinical trials (ganoderic acids A, C2, D, F, DM, X and Y). The related pharmacodynamic mechanisms and targeted signalling proteins were further analysed. Notably, the specific relationship between autophagy and apoptosis induced by ganoderic acid DM is summarized here for the first time.
... The HMBC correlations ( Figure 1) showed the coupling from H-14 (δ H 0.99) to C-1 (δ C 40.3), C-5 (δ C 77.9), C-6 (δ C 48.4), C-7 (δ C 54.0) and C-13 (δ C 24.7). These data resembled antrodin F (or gymnomitr-3-ene-9,15-diol) [8] and ganosinensine (or 9,15dihydroxygymnomitr-3-en-5-one) [9]. The difference was that a methylene, an oxygenated methine and an oxygenated quaternary carbon signal were obtained from 1 instead of the double bond and the ketone signals in those two compounds. ...
... The relative configuration of 1 was determined using the NOESY experiment. A NOESY cross peak between H-12β and H-13β indicated that two 5-member rings were in the cis-fused conformation, which was consistent with the common gymnomitrane structure [8][9][10]. The NOE cross-peaks between H-13/H-14, H-1/H-13, H-1/H-12 and H-2/H-12 suggested the β-orientation of 14-CH 3 and H-2. ...
... Due to the low amount, the absolute configuration of 1 remains undetermined by the present data. It is noted that gymnomitrane sesquiterpenes are mainly found in the liverwort [10] and only ganosinensine has been identified in Ganoderma sinense [9]. In the present study, the new gymnomitrane-3α,5α,9β,15-tetrol was isolated from G. lucidum. ...
A new gymnomitrane-type sesquiterpenoid, gymnomitrane-3α,5α,9β,15-tetrol (1), was isolated from the fruiting body of Ganoderma lucidum. Its structure was elucidated using spectroscopic methods. This compound significantly inhibited the growth of epidermal growth factor receptor-tyrosine kinase inhibitor EGFR-TKI-resistant human lung cancer A549 and human prostate cancer PC3 cell lines.
... HREIMS analyses showed that molecular formulas of leucocontextins J − N (10)(11)(12)(13)(14) were C 32 H 44 O 9 , C 32 H 46 O 9 , C 32 H 44 O 9 , C 32 H 42 O 9 and C 32 H 46 O 8 , respectively. The 1D NMR data of 10-14 indicated that these five compounds were analogs corresponding to compounds 1, 3, 4, 7 and 9 (Tables 2, 3, and 5), except for the substituent of acetoxy group at C-12 of 10-14. ...
... Leucocontextin R (18) (Tables 3 and 5) revealed a similar structure to ganoderiol J [14], except for an extra hydroxy at C-11 of 18 which was confirmed by the key HMBC correlations of H-11 (δ H 4.51)/ C-9 (δ C 158.9) and 1 H-1 H COZY correlations of H-11 (δ H 4.51)/H-12 (δ H 2.51, 1.85) (Fig. 2). The orientation of 11-OH was α according to the correlations between H-11 (δ H 4.51) and Me-18 (δ H 0.67) in the ROESY spectrum (Fig. 2). ...
... H NMR spectral data of compounds[13][14][15][16][17][18] J in Hz]. ...
... The 1 H, 1 H COSY spectrum of compound 1 ( Figure 2) revealed an extended spin system over four aliphatic methines and ending with one aliphatic methylene. By comparing the 1 H and 13 C NMR data (Table 1) of the sugar moiety with that reported for a related fungal lanostanoside, ganosinoside A [26] and other glycosidic moieties [27], it was confirmed to be a β-ᴅ-glucopyranosyl residue. The HMBC spectrum of compound 1 ( Figure 2) also revealed key correlations from two methylene groups at δ H 2.65/2.69 ...
... Hence, their positions were notably confirmed to be at C-3 and C-21, respectively. The ᴅ-configuration of the β-glucopyranosyl unit was assumed to be the one found in related fungal lanostanosides namely; ganosinoside A from Ganoderma sinense [26], fomitosides I and J from Fomitopsis pinicola [34]. Concerning the configuration at C-3', it was assigned as S by careful comparison of the 1 H and 13 C NMR data of compound 1 with those of related lanostane derivatives comprising the 3-hydroxy-3-methylglutaryl moiety produced by some fungi including Fomitopsis pinicola [23], Piptoporus betulinus [13], and Pholiota populnea [35]. ...
Chemical exploration of solid-state cultures of the polypore Fomitopsis carnea afforded two new C31 lanostane-type triterpenoid glycosides, forpiniosides B (1) and C (2) together with two known derivatives, namely 3-epipachymic acid (3) and (3α,25S)-3-O-malonyl-23-oxolanost-8,24(31)-dien-26-oic acid (4). The structures of the isolated compounds were established based on HRESIMS and extensive 1D and 2D NMR experiments. All the isolated compounds were assessed for their antimicrobial and cyto-toxic activities. Among the tested compounds, forpinioside B (1) exhibited significant antimicrobial activity against Staphylococcus aureus and Bacillus subtilis at MIC values comparable to gentamycin and oxytetracycline (positive controls), respectively.
... 8a,9a-Epoxy- 3,7,11,15,23-pentaoxo-5a-lanosta-26-oic acid (159) has four keto groups in the lanostane skeleton, a fifth group in the side-chain and an epoxy group between C8 and C9 ( Joseph et al., 2011a). Liu et al., 2012b;Nishitoba et al., 1985bNishitoba et al., , 1987c). Applanoxidic acid A (139), E (141) and G (145) have hydroxyl substitutions at C15 whereas applanoxidic acid B (140), C (143), D (144), F (142) and H (146) are 15-keto analogs (Chairul et al., 1994). ...
... In most cases, the genus name (Ganoderma) or source species names were used to coin trivial names of isolated secondary metabolites (ganoderic acid (Ganoderma), lucidenic acid (lucidum), cochlate (cochlear), fornicatin (fornicatum), australic acid (australe)) (Table 1, Fig. 1, Table S1). In some cases, compounds with sequen- tial trivial names do not show structural similarities (ganoderic acid Jd (312) isolated from G. sinense is not a C30 lanostane, but a C27 lucidenic acid type molecule) ( Liu et al., 2012b). Moreover, trivial names of ganoderic acids and lucidenic acids are confusing because identical compounds were given different names or different com- pounds were named identically. ...
... The triterpene-containing EtOAc and n-BuOH fractions were repeatedly purified by column chromatography over silica gel, MCI gel, ODS gel, Sephadex LH-20, and preparative HPLC to afford 20 nortriterpenoids, including six new compounds (1)(2)(3)(4)(5)(6) and nine known compounds (7)(8)(9)(10)(11)(12)(13)(14)(15). By comparison of spectroscopic data with those reported in literature, the known compounds were identified as lucidone A (7) [14], lucidone B (8) [14,15], lucidone H (9) [16], lucidone E (10) [9], lucidone F (11) [9], lucidone D (12) [9], lucidone C (13) [15], ganoderense F (14) [17], and ganosineniol A (15) [18]. Structural elucidation of new compounds was as follows. ...
... The triterpene-containing EtOAc and n-BuOH fractions were repeatedly purified by column chromatography over silica gel, MCI gel, ODS gel, Sephadex LH-20, and preparative HPLC to afford 20 nortriterpenoids, including six new compounds (1-6) and nine known compounds (7)(8)(9)(10)(11)(12)(13)(14)(15). By comparison of spectroscopic data with those reported in literature, the known compounds were identified as lucidone A (7) [14], lucidone B (8) [14,15], lucidone H (9) [16], lucidone E (10) [9], lucidone F (11) [9], lucidone D (12) [9], lucidone C (13) [15], ganoderense F (14) [17], and ganosineniol A (15) [18]. Structural elucidation of new compounds was as follows. ...
Ganoderma resinaceum
is usually used as ethnomedicine for immune-regulation, hyperglycemia, and liver disease. To date, only a few chemical constituents have been reported fromG.resinaceum. In this study, fifteen nortriterpenoids including six new nortriterpenoids (1-6) and nine known analogs (7-15), were separated and purified from the fruiting bodies ofG.resinaceum. New compounds were identified as lucidone I (1), lucidone J (2), lucidone K (3), lucidone I (4), ganosineniol B (5), and ganosineniol C (6), based on analysis of extensive spectroscopic data (high resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), infrared (IR), and ultraviolet (UV)). The known compounds were assigned as lucidone A (7), lucidone B (8), lucidone H (9), lucidone E (10), lucidone F (11), lucidone D (12), lucidone C (13), ganoderense F (14), and ganosineniol A (15), by comparing their spectroscopic data with those reported in the literature. Compounds3,4, and7-13were examined forα-glucosidase inhibitory activity and display no significant activity, but the finding may support that the side chain of ganoderma triterpenoids played an important role inα-glucosidase inhibitory activity.
... Compound 2a also displayed potential cardiomyocyte protection from ischaemia/reperfusion injury (Gao et al., 2018). Liu et al. (2012) isolated various terpenoids from the mushroom and subjected them to anti-proliferative assays. Notably, ganoderic acid Jc exhibited a selective inhibitory activity against HL-60 cells (IC 50 = 8.30 μM), while ganoderiol E portrayed cytotoxic potency against MCF-7 cells (IC 50 = 6.35 μM). ...
Mushrooms have long been recognized for their remarkable health benefits, where the genus Ganoderma is considered as one of the most extensively studied groups of medicinal macrofungi. The taxon comprises over 130 species found worldwide, especially in Asia, many of which have been valued in traditional medicine. Despite such rich diversity and ethnic importance, majority of the research has primarily focused on Ganoderma lucidum; while numerous other potent members remain overlooked in the scientific community. Some of such matrices include Ganoderma atrum, G. australe, G. carnosum, G. colossus, G. curtisii, G. formosanum, G. leucocontextum, G. neo-japonicum, G. praelongum, G. pfeifferi, G. resinaceum, and G. sinense that have demonstrated significant medicinal attributes. These encompass antioxidant, antimicrobial, cytotoxic, anti-tumor, anticancer, anti-diabetic, cholesterol-lowering, immune-modulating, hepatoprotective properties and more. The present review aims to shed light on the therapeutic potential of these underappreciated Ganoderma spp. emphasizing need for more comprehensive research. Future investigations should thus be directed towards exploring their bioactive compounds, mechanisms of action, clinical studies, and potential applications in addressing various health conditions.
... G. sinense is a precious edible and medicinal fungus that has been used to improve human health (Zheng et al., 2018). G. sinense contains a variety of bioactive components, such as polysaccharides (Han et al., 2021), immunomodulatory proteins (Han et al., 2010), terpenoids (Liu, Wang, Li, Luo, & Qiu, 2012), ergosterols (Mei et al., 2019), and farnesyl phenols (Gao et al., 2017), etc. These bioactive components endow G. sinense with anti-tumor (Han et al., 2021), immunomodulation , anti-aging (Teseo et al., 2021), anti-inflammatory (Mei et al., 2019), and antioxidant properties . ...
... These compounds are unique, with a lanostane-type triterpenoid having farnesyl hydroquinone moieties. 31,32 Several MD factors were analyzed, such as the RMSD, RMSF, average center-of-mass distance between ligand and protein, hydrogen bonds (protein-ligand), radius of gyration of protein-ligand complexes, and SASA. In both cases, the RMSD values moving from 0.2 to 0.6 nm denoted the average variance between the atoms of the trajectory frames, which indicated that the protein-ligand complexes remained constant throughout the simulation time. ...
Background: Staphylococcus aureus is a nosocomial pathogen responsible for many serious infectious diseases in humans. Finding the anti- S. aureus agents is a time-consuming and costly process. Recently, computational methods have provided a better understanding of the interactions between herbal medicine drug targets to help clinical practitioners rationally design herbal formulae. Methods: In this study, molecular docking simulation was applied to screen a list of natural secondary metabolites from Ganoderma sp. on the protein target S. aureus sortase A. Molecular dynamics models were used to assess the stability of protein–ligand complexes during the first 100 ns. To validate the computational results, 2 Ganoderma species, G. multiplicatum VNKKK1901 and G. sinense VNKKK1902, were tested for antibacterial activity against S. aureus using the disk diffusion method. Results: The results showed that, among the selected compounds, ganosinensin B and ganosinoside A generated the highest binding energy on S. aureus sortase A, and demonstrated strong and stable binding capacity to proteins. In addition, the extracts of G. sinense VNKKK1902 and G. multiplicatum VNKKK1901 were bactericidal, with minimum bactericidal concentration (MBC)/minimum inhibitory concentration (MIC) ratios of 2. Conclusion: Our findings provide the first scientific report on the antibacterial activity of Ganoderma sp., which contain 2 promising compounds, ganosinensin B and ganosinoside A, as potential hits for developing novel drugs capable of supporting treatment of S. aureus infection.
... GAs are predominantly isolated from mushroom biomass, as direct chemical synthesis is greatly hindered by their stereochemical complexity 5 . However, the GA content of Ganoderma is extremely low [6][7][8][9][10][11][12] , and increasing the content of specific GAs is difficult due to technical challenges with the genetic manipulation of Ganoderma 13 and a lack of knowledge of GA biosynthesis. Moreover, the mushroom-farmingbased supply chain is susceptible to the climate 14 , insect pests 15 , the availability of agricultural land 16 , and global crises, including the ongoing coronavirus disease 2019 pandemic 17,18 . ...
Type II ganoderic acids (GAs) produced by the traditional medicinal mushroom Ganoderma are a group of triterpenoids with superior biological activities. However, challenges in the genetic manipulation of the native producer, low level of accumulation in the farmed mushroom, the vulnerabilities of the farming-based supply chain, and the elusive biosynthetic pathway have hindered the efficient production of type II GAs. Here, we assemble the genome of type II GAs accumulating G. lucidum accession, screen cytochrome P450 enzymes (CYPs) identified from G. lucidum in baker’s yeast, identify key missing CYPs involved in type II GAs biosynthesis, and investigate the catalytic reaction sequence of a promiscuous CYP. Then, we engineer baker’s yeast for bioproduciton of GA-Y (3) and GA-Jb (4) and achieve their production at higher level than those from the farmed mushroom. Our findings facilitate the further deconvolution of the complex GA biosynthetic network and the development of microbial cell factories for producing GAs at commercial scale. The biosynthetic pathway of type II ganoderic acids (GAs) in Ganoderma lucidum, a traditional medicinal mushroom, is unknown. Here, the authors assemble the genome of type II GAs accumulating accession, identify CYPs involving in type II GAs biosynthesis, and achieve their production in engineered baker’s yeast.
... Seventeen ganoderic acids were identified in G. lingzhi including well-known ganoderic acids A, T, Me, and C2. Some less-known ganoderic acids, AP2 and GS-3, were also identified in G. lingzhi which were previously found in Ganoderma applanatum [33] and Ganoderma sinense [34], respectively. In addition, we identified ganodermanontriol, ganoderenic acid C, and a new special GA, ganochlearic acid A (C24H34O5), which is a rearranged hexanorlanostane triterpenoid featuring a γ-lactone ring (A ring) and a fivemembered carbon ring (B ring) (Figure 4 compound 20). ...
Ganoderma (Ganodermaceae) is a genus of edible and medicinal mushrooms that create a diverse set of bioactive compounds. Ganoderma lingzhi has been famous in China for more than 2000 years for its medicinal properties. However, the genome information of G. lingzhi has not been characterized. Here, we characterized its 49.15-Mb genome, encoding 13,125 predicted genes which were sequenced by the Illumina and PacBio platform. A wide spectrum of carbohydrate-active enzymes, with a total number of 519 CAZymes were identified in G. lingzhi. Then, the genes involved in sexual recognition and ganoderic acid (GA, key bioactive metabolite) biosynthesis were characterized. In addition, we identified and deduced the possible structures of 20 main GA constituents by UPLC-ESI-MS/MS, including a new special ganochlearic acid A. Furthermore, 3996 novel transcripts were discovered, and 9276 genes were predicted to have the possibility of alternative splicing from RNA-Seq data. The alternative splicing genes were enriched for functional categories involved in protein processing, endocytosis, and metabolic activities by KEGG. These genomic, transcriptomic, and GA constituents’ resources would enrich the toolbox for biological, genetic, and secondary metabolic pathways studies in G. lingzhi.
... Terpenoids are difficult to synthesize chemically due to their complex chemical structures and easily pollute the environment (Xiao and Zhong 2016). In addition, traditional extraction methods to obtain terpenoids from G. sinense often result in the loss of active ingredients and waste of resources (Liu et al. 2012). Therefore, the use of genetic engineering technology to obtain high-yielding strains of G. sinense sesquiterpene synthase is the focus of research. ...
Ganoderma sinense, with more than 2000 years of medicinal history, is a fungus of the basidiomycetes that is rich in polysaccharides and terpenoids. However, the biosynthesis of terpenes, especially sesquiterpenes, has been little studied. The functional identification of sesquiterpene synthases from G. sinense is of great significance to the study of fungal terpenoid biosynthesis and regulation. Our research group has completed the functional characterization of 21 sesquiterpene synthase genes from G. sinense. It was found that gleenol, biosynthesis of which is catalyzed by the sesquiterpene synthase GsSTS26 and GsSTS27, has the functions of killing termites, antihelminth, and plant growth regulation. In the unmodified E. coli Rosetta (DE3) strain, the content of gleenol produced by sesquiterpene synthase from G. sinense is low, which makes it difficult to meet the demand of industrial production and the market. Therefore, it is of great significance to obtain high-yielding strains by means of synthetic biology. In this study, we constructed eight recombinant strains by using tandem gene expression and promoter engineering, and the content of gleenol was increased by up to 23-fold. In this study, we realized the de novo synthesis of gleenol in E. coli and provided a basis for the biosynthesis of terpenoids in basidiomycetes.
Key points
• Eight recombinant expression systems were constructed by using tandem genes and promoter engineering.
• The recombinant strain promoted the efficient production of gleenol in E. coli Rosetta (DE3).
• The recombinant strain achieved de novo production of gleenol in E. coli.
Graphical abstract
... Sesquiterpenoids are representative terpenoid molecules that are widely distributed in plants, microbes, and microorganisms. Over 300 natural sesquiterpenoid skeletons have been reported so far (Cane, 1999;Liu et al., 2012), and novel skeletons are being discovered on a regular basis. The reported compounds have been found to have extensive bioactivities, such as anti-inflammatory (Chang et al., 2020), lipid regulatory (Zhu et al., 2020;Yin et al., 2021), antiviral (Liu et al., 2021), anti-proliferative (Wu et al., 2021), and proangiogenic (Han et al., 2022) activities. ...
Two new sesquiterpenoids, curcumanes E (1) and F (2), were isolated from the rhizome of Curcuma longa, and their structures and absolute configurations were examined using extensive spectroscopic analyses and ECD calculations. Interestingly, compounds 1 and 2 are diastereoisomers possessing a rare sesquiterpenoid skeleton that has been reported only once before. Both curcumanes E and F exhibit significant vasorelaxant effects against KCl-induced contraction of rat aortic rings, with EC50 values of 5.10 ± 0.79 and 5.58 ± 1.77 μM, respectively. These findings enrich the data concerning this rare type of sesquiterpenoids and further indicate that these rare sesquiterpenoids can effectively reduce blood pressure.
... In addition, by comparing the spectroscopic data with data reported in the literature, eight known compounds were identified as 16α-hydroxy-3-oxolanosta-7,9(11),24-trien-21-oic acid (14) (de Silva et al., 2006), 3β-hydroxylanosta-7,9(11),24-trien-21-oic acid (15) (Tai et al., 1993), 3β,16α-dihydroxylanosta-7,9(11),24-trien-21-oic acid (16) (Nukaya et al., 1996), 3-oxolanosta-7，9(11),24-trien-21-oic acid (17) (Akihisa et al., 2004), 3β-hydroxylanosta-8,24-dien-21-oic acid (18) (Keller et al., 1996), boscartene D (19) (Wang et al., 2016), pinicolic acid A (20) (Ahamd et al., 1976), ganosinoside A (21) (J.-Q. Liu, Wang, Li, Luo and Qiu, 2012), and pinicolic acid (22) (Rösecke and König, 1999). ...
Thirteen previously undescribed lanostane triterpenoids, as well as nine known lanostane triterpenoids, were isolated from the fruiting bodies of Fomitopsis pinicola (Sw.) P. Karst. Their structures and absolute configurations were characterized by extensive analysis of spectroscopic data and single-crystal X-ray diffraction. Nor-pinicolic acids A-F possess unusual C-25-C-27 nor-lanostane skeletons, which were first reported from F. pinicola. Anti-inflammatory assays indicated that pinicopsic acid F and 16α-hydroxy-3-oxolanosta-7,9(11),24-trien-21-oic acid showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 cells, with IC50 values of 24.5 and 25.7 μM, respectively.
... The more weight of Ganoderma mushroom is due to its high water content up to 90%, which makes extracts of mushroom dehydrated powder and residual 10% of its mass consist of protein (10-40%), carbohydrate (3-28%), fiber (3-32%), fat (28%), and ash (8-10%). Besides, various other compounds such as provitamin D2 [9], C19 fatty acids [10], and essential nutrients such as copper and zinc [11] have also been found to be present. With the minerals potassium, calcium, phosphorous, magnesium, selenium, iron, zinc, and copper represent most of the mineral content [12,13]. ...
Ganoderma a traditional Chinese medicine popularly used for complementary cancer therapy and longevity for centuries. The vast amount of study has been performed on the medicinal properties of Ganoderma lucidum. G. lucidum contains various compounds with a high grade of biological activity, which increase the immunity. Several of these substances belong to the triterpenoids and polysaccharides. Proteins, sterols, phenols, lipids, etc., are also present. Ganoderma triterpenes are important secondary metabolites of G. lucidum. Ganoderma triterpenes are lanostane tetracyclic terpenes which have been reported to possess antioxidant, antitumor, anti-human immunodeficiency virus, anticancer, anti-inflammation, cytotoxic, hepatoprotective, and neuroprotective activities. This review deals with most important triterpenes isolated from Ganoderma and their therapeutic effects.
... For Ganoderma, triterpenoids are the major secondary metabolites and active substances [6]. e pioneering has isolated and identi ed more than 300 triterpenoids from the spores, fruiting bodies, and cultured mycelia of Ganoderma [7][8][9]. ...
Triterpenoids are the major secondary metabolites and active substances in Ganoderma, considered as the "marker compounds" for the chemical evaluation or standardization of Ganoderma. A response surface methodology was used to optimize the ultrasonic-assisted extraction of triterpenoids. The extraction rate was 7.338 ± 0.150 mg/g under the optimum conditions: 87% ethanol, ratio of solid to liquid (w : v) 1 : 28, and ultrasound extraction time 36 min. Based on the high sensitivity and selectivity of HPLC-LTQ-Orbitrap-MS
n
, 24 components of triterpenoids were tentatively identified in the negative mode. Then, the global chemical profiling consisting of HPLC and TLC fingerprints generated by ChemPattern™ software was developed for evaluation of Ganoderma species. For fingerprint analysis, 11 peaks of triterpenoids were selected as the characteristic peaks to evaluate the similarities of different samples. The correlation coefficients of similarity were greater than 0.830. The cluster analysis showed a clear separation of three groups, and 11 peaks played key roles in differentiating these samples. The developed global chemical profiling method could be applied for rapid evaluation, quality control, and authenticity identification of Ganoderma and other herbal medicines.
... All the reported gymnomitrane-type sesquiterpenes were isolated from lower polar essential oils or extracts of liverworts with chemotaxonomic importance 24,36-41 , except for three derivatives from fungal cultures 42,43 and fruiting bodies 44 and only one from a higher plant 45 . Compound 2 represents the first glycosidic gymnomitrane sesquiterpene. ...
Three new sesquiterpene glycosides, named codonopsesquilosides A−C (1−3), were isolated from an aqueous extract of the dried roots of Codonopsis pilosula. Their structures including absolute configurations were determined by spectroscopic and chemical methods. These glycosides are categorized as C15 carotenoid (1), gymnomitrane (2), and eudesmane (3) types of sesquiterpenoids, respectively. Compound 1 is the first diglycoside of C15 carotenoids to be reported. Compound 2 represents the second reported example of gymnomitrane-type sesquiterpenoids from higher plants. The absolute configurations were supported by comparison of the experimental circular dichroism (CD) spectra with the calculated electronic CD (ECD) spectra of 1−3, their aglycones, and model compounds based on quantum-mechanical time-dependent density functional theory. The influences of the glycosyls on the calculated ECD spectra of the glycosidic sesquiterpenoids, as well as some nomenclature and descriptive problems with gymnomitrane-type sesquiterpenoids are discussed.
... G. sinense contains triterpenes that have a farnesyl hydroquinone moiety and are named ganosinensins A-C (Sato et al., 2009). Another group has given the name ganosinensine to a structurally different sesquiterpenoid from G. sinense (Liu et al., 2012). ...
Ganoderma, a genus of mushrooms known for its long history of medicinal use, has gained increasing attention in recent years due to its potential health benefits. This review delves into the bioactive compounds found in Ganoderma and elucidates the intricate mechanisms underlying its immunomodulatory and anti-tumour activities. The diverse health-promoting effects of Ganoderma can be attributed to its decadent array of bioactive compounds, notably polysaccharides, and triterpenoids, which play a pivotal role. The ability of the mushroom to modulate the immune system, enhancing the activity of immune cells, such as natural killer cells and macrophages, is a central focus. Furthermore, we explore how Ganoderma exerts anti-tumour effects through the induction of apoptosis, inhibition of angiogenesis, and interference with various signalling pathways critical for cancer cell growth and metastasis. As research in this area continues to evolve, a comprehensive understanding of the potential of Ganoderma as a natural health supplement and its role in promoting well-being is emerging, offering promising avenues for further investigation and application in healthcare.
Ganoderma is the dried fruiting bodiy of Ganoderma lucidum (Leyss.ex Fr.) Karst. or Ganoderma sinense Zhao, Xu et Zhang, belonging to the family Polyporaceae, which grows mainly in tropical, subtropical, and temperate regions. As a traditional Chinese medicine, Ganoderma has been used in China for more than 2000 years because of its medicinal properties, such as relieving cough and asthma, providing nourishment, and strengthening. Currently, more than 470 natural compounds have been obtained from the fungus, mainly including terpenoids, steroids, alkaloids, phenols, and other types of compounds. Modern pharmacological studies have shown that Ganoderma has antitumor, anti-inflammatory, hypoglycemic, hypolipidemic, and immunomodulatory effects. It is mainly used in clinical practice for the treatment of Diabetic Nephropathy and malignant tumors, with few side effects and high safety. This paper reviews the progress of research on its chemical composition, pharmacological effects, and clinical applications, with the goal of providing a basis for the better development and utilization of Ganoderma.
Ganoderic acids (GA) are one of the important secondary metabolites acquired from Ganoderma lucidum (G. lucidum) with
a wide range of pharmacological activities and therapeutic efects on human ailments. They are triterpenes with four cyclic
and two linear isoprenes and products of the mevalonate pathway. GA serve as a valuable resource for the development of
new drugs; however, they are usually produced at very low concentrations and the producing mushroom requires tedious feld
cultivation for industrial application. Additionally, the magnitude of diferent types of GA isolated with diferent bioactivities reiterates the need to determine the basis of diversifcation. The elucidation of GA biosynthesis regulatory mechanisms
has attained heightened interest from scientists and warranted the emergence of various strategies to control production as
well as increase yield. In this review, we discuss important insights into the environmental and genetic regulation of GA
biosynthesis. We explore viable avenues for GA hyper-production and challenges in elucidating the diversifcation of GA.
Research progress of active compounds and biological activities of medicinal mushroom-Ganoderma spp., Hericium spp., Phellinus spp., and Cordyceps spp. were summarized systematically. The main active compounds of medicinal mushrooms included are polysaccharides, proteins, triterpenes, meroterpenoids, polyphenols and nitrogen-containing compounds. The biological activities of the compounds cover immunomodulatory activity, antitumor activity, hypoglycemic activity, hepatoprotective activity, and activity of regulation of intellectual flora.
Ganoderma lucidum is a famous edible and medicinal fungus. Through a bioactive phytochemical investigation of the ethanolic extracts of the fruiting bodies of G. lucidum, twenty-nine triterpenoids, including eleven previously undescribed triterpenoids, were isolated and characterized based on spectroscopic data. The inhibitory effects of all the triterpenes against fatty acid amide hydrolase (FAAH) were found to be in the range of 30–60% at 100 μM. Methyl ganoderate A displayed the strongest inhibitory activity (61%) against FAAH. Furthermore, all compounds displayed no cytotoxicity against LOVO and MCF-7 human cancer cells. Hence, our present study provides information about G. lucidum as a functional food or pharmaceutical supplement for the treatment of neuroinflammation.
Two new nor-triterpenoids ganodrenol A (1), B (2), and a new natural product ganodrenol C (3), along with three known nor-triterpenoids (4-6) were isolated from the fruiting bodies of Ganoderma lucidum. The chemical structures of these isolates were determined by 1 D and 2 D NMR, HRESIMS, and X-ray crystallography analysis. The inhibitory effects of isolated triterpenoids (1-6) against FAAH were evaluated by an in vitro assay, and compound 4 showed an inhibition rate of 70.27%. In addition, the cytotoxic effect of compounds (1-6) was evaluated against LOVO, MCF-7, and RAW264.7 cells, which displayed no significant cytotoxicity.
In this study, a high performance thin-layer chromatography/single quadrupole mass spectrometry QDa (HPTLC-QDa) method for robust authentication of Ganoderma lucidum, a popular and valuable herbal medicine, has been developed. This method is simple and practical, which allows direct generation of characteristic mass spectra from the HPTLC plates automatically with the application of in situ solvent desorption interface. The HPTLC silica gel plates were developed with toluene-ethyl formate-formic acid (5 : 5 : 0.2, V/V) and all bands were transferred to QDa system directly in situ using 80% methanol with 0.1% formic acid as desorption solvent. The acquired HPTLC-QDa spectra showed that luminous yellow band b3, containing ganoderic acid B/G/H and ganodeneric acid B, the major active components of Ganoderma, could be found only in G. lucidum and G. lucidum (Antler-shaped), but not in G. sinense and G. applanatum. Moreover, bands b13 and b14 with m/z 475/477 and m/z 475/491/495, respectively, could be detected in G. lucidum (Antler-shaped), but not in G. lucidum, thus allowing simple and robust authentication of G. lucidum with confused species. This method is proved to be simple, practical and reproducible, which can be extended to analyze other herbal medicines.
Terpenes, polyketides, and tannins are valuable chemical classes that are famous
for their varied biological activities such as being antioxidant, anticancer, antibiotic, and immunosuppressant agents. On the other hand, lichens and mosses are rich sources of biologically active compounds. However, rare studies have described neither the chemical analyses nor the biological activities of such samples. In this review, the chemical constitutions of five Japanese originated lichens and moss samples belonging to the species Candelariella vitellina, Lepraria incana, Dirinaria applanata, Brachythecium
velutinum, and Brachythecium rutabulum were described with focus on three chemical classes which are terpenes such as Dechloromycorrhizin A, Hericenone A, demethoxyviridin, Scytalidic acid, Ovellin B, Ceriporic acid B, Ganodermatriol,
Fomefficinic acid A, Ganoderol A, Ganoderol F; polyketides such as Chaetoquadrin A, Comazaphilone C, Hormothamnione, Arnottianamide, Avermutin, 4′- ydroxyphlebiarubrone, 4′-Hydroxyphlebiarubrone, Citropone A, Atrovenetin; and finally secondary metabolites (tannins) such as 5′ methoxydehydrodiconiferyl alcohol, ellagic acid 3,3′-di-O-methyl ether, 5,5′- dehydrodiferulic acid, 3,3′,4-tri-O-methylellagic acid, and 5′-
methoxydehydrodiconiferyl alcohol.
Ganoderma lucidum is one of the most famous medicinal fungi and is traditional Chinese medicine with various biological activities in Asian countries. To clarify its pharmacodynamic material basis, 15 lanostane triterpenoidswere obtained from the fruiting bodies of G. lucidum, including 8 previously undescribed lanostanoids. Their structures, including absolute configuration, were established based on ultraviolet, infrared, high-resolution electrospray ionisation mass spectrometry, 1D and 2D nuclear magnetic resonance, and X-ray crystallographic analysis. Ganoluciduone A was an unusual octonorlanostane, which was isolated from Ganoderma for the first time. In addition, the anti-inflammatory activities of all isolates were evaluated by observing their inhibitory effects on nitric oxide production in RAW264.7 cells activated by a lipopolysaccharide. Ganoluciduone B exhibited moderate inhibitory activity on nitric oxide production, with an inhibition rate of 45.5% at a concentration of 12.5 μM.
Extensive studies have revealed that triterpenoids, meroterpenoids, and polysaccharides are the main constituents of the well-known traditional Chinese medicinal mushroom Ganoderma. In this study, we report seven previously undescribed sesquiterpenoids, including six gymnomitranes (1–6) and a novel type of sesquiterpenoid (8), together with a polyketide (7) and a known steroid (9) from the fruiting bodies of Ganoderma lingzhi, a fungus used as traditional medicine and food supplement in East Asia for ages. The structures of 1–8 were deduced by analysis of spectroscopic data, X-ray single crystal diffractions and TDDFT/ECD calculations. Compound 8 possessed an unusual 14(7→6)-cuparane scaffold. Compound 9 exhibited weak cytotoxicity against the five human cancer cell lines HL-60, MCF-7, SW480, A549, and SMMC-7721 with IC50 values of 18.0–32.3 μM. A simple structure-activity-relationship (SAR) investigation by acetylating the 5-OH of 9 (9a) suggested that the 5-OH is essential for its cytotoxicity. Additionally, the biosynthetic pathways for compounds 2 and 8 are discussed.
Fomitopsis pinicola (Sw. Ex Fr.) Krast has been commonly used as a health food source and anti-tumor agent. To uncover bioactive key composition of F. pinicola, in our study, we investigated the chemical constituents of methanol extract of F. pinicola and thirty-five lanostane-type tritetpenoids, including thirteen new compounds (1‒13) and twenty-two known analogues (14‒35) were isolated. Among them, compounds 1‒9 were C30 lanostane triterpenoids and triterpene sugar esters, while compounds 10‒13 were C31 triterpenoids and triterpene sugar esters. Their structures and absolute configurations were elucidated by extensive 1D, 2D NMR, MS and IR spectra. Furthermore, cytotoxic activities of all isolates against five human tumor cell lines (HL-60, A549, SMMC-7721, MCF-7 and SW480) were evaluated. The results showed that compounds 12, 14, 17, 18, 22 and 23 displayed cytotoxic effects against five human tumor cell lines with IC50 values ranging from 3.92‒28.51 μM. Meanwhile, compounds 9 and 35 exhibited selected inhibitory activities against HL-60, SMMC-7721 and MCF-7 with the IC50 values in the range of 13.57‒36.01 μM. Furthermore, the flow cytometry analysis revealed that compounds 17, 22 and 35 induced apoptosis in HL-60 cell lines. Their structure-activity relationships were preliminarily reported. These findings indicate the vital role of triterpenoids and their glycosides in explaining anti-tumor effects of F. pinicola and provide an important evident for the further development and utilization of this fungus.
Ganoderma sinense is a Chinese unique medicinal fungus that has been used in folk medicine for thousands of years. Polysaccharides are considered to be biologically active ingredients due to their immune-modulating functions. Previously we found that GSP-2, a new polysaccharide isolated from Ganoderma sinense, exerts an immunomodulatory effect in human peripheral blood mononuclear cells but the underlying mechanism is unclear. The present study aimed to investigate how GSP-2 triggers immunologic responses and the implicated signaling pathways. GSP-2 effects were investigated both in a macrophagic cell line, RAW264.7, and in primary macrophages. Moreover, the molecular basis of GSP-2 recognition by immune cells, and the consequent activation of signaling cascades, were explored by employing recombinant human HEK293-TLR-Blue clones, individually overexpressing various Toll-like receptors. GSP-2 dose-dependently induced the overexpression of Toll-like receptor 4 (TLR4) but did not affect the expression of other TLRs. Moreover, GSP-2 induced TNFα secretion in primary macrophages from wild-type, but not TLR4-knockout mice. In addition, GSP-2 upregulated TLR4 protein expression and activated the MAPK pathway in RAW246.7 macrophages. Finally, GSP-2 induced the production of the cytokines TNFα, IL1β, and IL6. Our data demonstrated that GSP-2 was specifically recognized by TLR4, promoting cytokine secretion and immune modulation in macrophages.
Ganoderma lucidum, as food, tea, dietary supplement, and medicine, is widely used in China and Eastern Asian countries. In order to discover its anti-inflammatory constituents and provide some references for the usage of G. lucidum and G. sinense, two official species in China, the fruiting bodies of G. lucidum were studied, leading to the isolation of six new triterpenoids (1-6) and 27 known analogues (7-33). Compound 4 exhibited the most potent inhibition on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. The production of IL-6 and IL-1β, as well as the expression of iNOS, COX-2 and NF-κB were dose-dependently reduced by 4. The phosphorylations of IκBα and IKKβ in LPS-induced macrophage cells were blocked by 4. Therefore, 4 could be used as a potential anti-inflammatory candidate and the total triterpenoids might be developed as value-added functional food for the prevention of inflammation. In combination of previous studies, it should be cautious for the interchangeable usage of G. lucidum and G. sinense.
Candelariella vitellina is common green-yellow lichen found on barks, wood, and rocks in Japanese forests. To investigate the mechanism of its anticancer potential, C. vitellina (80%
MeOH/H2O) extract was prepared. High-performance liquid chromatography–high-resolution electrospray ionization mass spectrometry analysis revealed seven new compounds and 11 natural compounds of terpenes and polyketides. In vitro cytotoxicity analysis of Caco-2 cells exhibited an IC50 of 125 ± 4.1 µg/mL. No significant cytotoxicity was observed in vitro in normal human peripheral lymphocytes. Both the IC25 and IC50 were determined to explore the potent anticancer potential in this study. C. vitellina exhibited a mitochondrial P53-independent apoptotic effect with negative P53 expression and an elevated BAX/BCL2 ratio as well as upregulated CASP3 mRNA expression. Similarly, in vivo analysis showed the same pattern of anticancer potential but was dependent on the P53 expression. Furthermore, C. vitellina induced antioxidative conditions in vitro and in vivo. The decreased invasion of tumor cells in vivo and increased apoptotic features in vitro and in vivo suggest the moderate to strong apoptotic anticancer potential of C. vitellina. However, further studies are needed to determine the extent
and mechanism of action on different cell lines to support the anticancer properties of this lichen.
Ganoderic acids, a group of oxygenated lanostane-type triterpenoids, are the major bioactive compounds produced by the well-known medicinal macro fungus Ganoderma lucidum. More than 150 ganoderic acids have been identified, and the genome of G. lucidum has been sequenced recently. However, the biosynthetic pathways of ganoderic acids have not yet been elucidated. Here, we report the functional characterization of a cytochrome P450 gene CYP512U6 from G. lucidum, which is involved in the ganoderic acid biosynthesis. CYP512U6 hydroxylates the ganoderic acids DM and TR at the C-23 position to produce hainanic acid A and ganoderic acid Jc, respectively. In addition, CYP512U6 can also hydroxylate a modified ganoderic acid DM in which the C-3 ketone has been reduced to hydroxyl by the sterol reductase ERG27 from Saccharomyces cerevisiae. An NADPH-dependent cytochrome P450 reductase from G. lucidum was also isolated and characterized. These results will help elucidate the biosynthetic pathways of ganoderic acids.
Ganoderma leucocontextum is a well‐known medicinal mushroom cultivated in the Tibet Plateau of China. Chemistry investigation on the fruiting bodies of this mushroom resulted in the isolation of sixteen secondary metabolites including three new lanostane triterpenes, ganoleucoins Q‐S (1‐3), as well as thirteen known compounds (4‐16). The structures of compounds 1‐3 were determined by NMR, MS, CD spectral analysis and chemical derivation method. The neuroprotective effects of compounds 1‐16 were tested on PC12 cells. Compounds 1 and 2 showed protective effects against the H2O2 induced damage with the survival rate of 83.19 ± 0.92%, 73.37 ± 1.25% at the concentration of 200 μM, respectively. Meanwhile, compounds 1 and 2 induced neurite outgrowth at 50‐200 μM. The results from this study suggested that G. leucocontextum and its metabolites may be potential functional food ingredients for the prevention of neurodegenerative diseases.
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The genus Ganoderma (Ganodermataceae) has a long history in traditional medicine to improve longevity and health in Asia. Ganoderma has been widely used in multiple therapeutic activities as well as dietary supplements to prevent and treat many diseases. Several classes of bioactive substances have been isolated and identified from Ganoderma, such as polysaccharides, triterpenoids, nucleosides, sterols, fatty acids, protein and alkaloids. There are numerous research publications, which report the abundance and variety of biological actions initiated by the metabolites of Ganoderma. Investigation on different metabolic activities of Ganoderma species has been performed both in vitro and in vivo. In many cases, however, it has been questioned whether Ganoderma is solely a nourishment supplement for wellbeing or merely a helpful "medication" for restorative purposes. There has been no any conclusive report of human trials using Ganoderma species as a direct control agent for diseases. In addition, there is no evidence supporting the usage of Ganoderma species (excluding G. lucidum) as potential supplements for cancer or other diseases in humans since no preclinical trials have been performed up to date. In this review, the beneficial medicinal properties of several species of Ganoderma (excluding G. lucidum) and their secondary metabolites are discussed. Ganoderma species can be used as a therapeutic drug, but more direct scientific evidence should be made available in the future. The efficiency of Ganoderma in clinical treatments should be substantiated with more biomedical research and their true impact assessed on human health with more standardized clinical evaluations so that the feasibility of biologically active extracts of Ganoderma species in alternative treatments can be recommended.
Natural products and their derivatives have played a prominent role in the history of drug discovery and remain the most attractive source of potential drugs because of their structural complexity and diversity. Edible and medicinal fungi have been shown to have profound health-promoting benefits and were recognized as an important source of natural products with diverse structures and distinct pharmacological potential. There are about 10,000 fungi species and 473 medicinal fungi species in China. The fruiting bodies of these mushrooms were used in Chinese traditional medicine to treat various diseases. Recently, chemical investigation of edible and medicinal fungi collected in China led to isolation and identification of a huge number of bioactive compounds with various bioactivities including antibacterial, antioxidant, anticancer, antiplasmodial, antiproliferative, antifibrotic, and neurite outgrowth-promoting activities. In this chapter, we review the studies on isolation, structural elucidation and biologically activities of bioactive compounds derived from edible and medicinal fungi conducted by Chinese scientists after 2007. Selected compounds with unique structural features and promising bioactivities have been described herein on the basis of structural types. The main types included are terpenes, meroterpenoids, polyketides, and alkaloids. A table that lists the name of fungi species, bioactive compounds, and medicinal properties is given along with 109 references.
Secondary metabolites of higher fungi (mushrooms) are an underexplored resource compared to plant-derived secondary metabolites. An increasing interest in mushroom natural products has been noted in recent years. This chapter gives a comprehensive overview of the secondary metabolites from higher fungi, with 765 references highlighting the isolation, structure elucidation, biological activities, chemical syntheses, and biosynthesis of pigments, nitrogen-containing compounds, and terpenoids from mushrooms. Mushroom toxins are also included in each section.
Ganoderma duripora is widely circulated in the Chinese herbal medicine market, although the chemical constituents of this fungus are remain poorly characterized. Phytochemical investigation of the EtOH extract of the fruiting body of G.duripora resulted in the isolation of two trace triterpenoids, named ganoduritriol A and B, and their structures were determined by a combination of 1D, 2D NMR and UPLC-TOF-MS.
Two new triterpenes (1–2) and seven steroids (3–9) were isolated from the fruiting bodies of Ganoderma duripora. Structure elucidation of these compounds was generated by a combination of spectroscopic means (HRTOFMS, ¹H and ¹³C NMR). There are significant differences between the compounds isolated from Ganoderma duripora and from the other Ganoderma species, suggesting that we need to reconsider the classification of G. duripora according to the taxonomy of chemistry.
Seven new compounds including four lanostane triterpenoids, lucidenic acids Q-S (1-3) and methyl ganoderate P (4), and three triterpene-farnesyl hydroquinone conjugates, ganolucinins A-C (5-7), one new natural product ganomycin J (8), and 73 known compounds (9-81) were isolated from fruiting bodies of Ganoderma lucidum. The structures of the compounds 1-8 were determined by spectroscopic methods. Bioactivities of compounds isolated were assayed against HMG-CoA reductase, aldose reductase, α-glucosidase, and PTP1B. Ganolucidic acid η (39), ganoderenic acid K (44), ganomycin J (8), and ganomycin B (61) showed strong inhibitory activity against HMG-CoA reductase with IC50 of 29.8, 16.5, 30.3 and 14.3μM, respectively. Lucidumol A (67) had relatively good effect against aldose reductase with IC50 of 19.1μM. Farnesyl hydroquinones ganomycin J (8), ganomycin B (61), ganomycin I (62), and triterpene-farnesyl hydroquinone conjugates ganoleuconin M (76) and ganoleuconin O (79) possessed good inhibitory activity against α-glucosidase with IC50 in the range of 7.8 to 21.5μM. This work provides chemical and biological evidence for the usage of extracts of G. lucidum as herbal medicine and food supplements for the control of hyperglycemic and hyperlipidemic symptoms.
Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as cytotoxicity, immunomodulation, and anti-inflammation. Some of them also have interesting effects on metabolism and anti-infectious properties. This review will compile chemical data, biological effects, and mechanisms on the most relevant lanostanoids isolated from fungi, such as those from Ganoderma lucidum, Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and other.
Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as cytotoxicity, immunomodulation, and anti-inflammation. Some of them also have interesting effects on metabolism and anti-infectious properties. This review will compile chemical data, biological effects, and mechanisms on the most relevant lanostanoids isolated from fungi, such as those from Ganoderma lucidum, Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and other.
Six new lanostane-type triterpenoids, namely leucocontextins S–X (1–6), together with twelve known compounds, were isolated from the fruiting bodies of Ganoderma leucocontextum. Their structures were established by MS and NMR data.
Graphical Abstract
Sixteen new lanostane triterpenes, ganoleucoins A-P (1-16), together with 10 known tripterpenes (17-26), were isolated from the cultivated fruiting bodies of Ganoderma leucocontextum, a new member of the Ganoderma lucidum complex. The structures of the new compounds were elucidated by extensive spectroscopic analysis and chemical transformation. The inhibitory effects of 1-26 on HMG-CoA reductase and α-glucosidase were tested in vitro. Compounds 1, 3, 6, 10-14, 17, 18, 23, 25, and 26 showed much stronger inhibitory activity against HMG-CoA reductase than the positive control atorvastatin. Compounds 13, 14, and 16 presented potent inhibitory activity against α-glucosidase from yeast with IC50 values of 13.6, 2.5, and 5.9 μM, respectively. In addition, the cytotoxicity of 1-26 was evaluated against the K562 and PC-3 cell lines by the MTT assay. Compounds 1, 2, 6, 7, 10, 12, 16, 18, and 25 exhibited cytotoxicity against K562 cells with IC50 values in the range 10-20 μM. Paclitaxel was used as the positive control with an IC50 value of 0.9 μM. This is the first report of secondary metabolites from this medicinal mushroom.
The traditional Chinese medicines (TCMs) are essential components of alternative medicines. Many TCMs are known to alter the expression of hepatic drug-metabolizing enzymes and transporters. The molecular mechanism by which TCMs and/or their constituents regulate enzyme and transporter expression, however, has remained largely unknown. In this report, we show that two TCMs, Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selected constituents activate the xenobiotic orphan nuclear receptor pregnane X receptor (PXR). Treatment with TCM extracts and the Schisandrol and Schisandrin constituents of Wu Wei Zi induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays and in primary hepatocyte cultures. The affected enzymes and transporters include CYP3A and 2C isozymes and the multidrug resistance-associated protein 2. In transient transfection and reporter gene assays, the Schisandrin constituents of Wu Wei Zi had an estimated EC50 of 2 and 1.25 microM on hPXR and mPXR, respectively. Interestingly, mutations that were intended to alter the pore of the ligand-binding cavity of PXR had species-specific effects on the activities of the individual Schisandrols and Schisandrins. In rats, the administration of Wu Wei Zi and Gan Cao increased the metabolism of the coadministered warfarin, reinforcing concerns involving the safe use of herbal medicines and other nutraceuticals to avoid PXR-mediated drug-drug interactions. Meanwhile, the activation of PXR and induction of detoxifying enzymes provide a molecular mechanism for the hepatoprotective effects of certain TCMs.
Two novel lanostane-type triterpenes, Ganolactone B and Ganoderiol A triacetate, were isolated from the fruiting bodies of G. sinense, together with six known compounds. The structures of the two new triterpenes were determined as 3beta,7beta- dihydroxy-11,15-dioxo-lanosta-8-en-24-->20 lactone (1) and 3beta,24,26-triacetoxy-5alpha-lanosta-7,9(11)-dien-25-ol (2), respectively, by chemical and spectroscopic means.
Objective To study the chemical constituents from the fungal fruiting bodies of Ganoderma sinense. Methods Individual constituents, isolated and repeatedly purified on silica gel and Sephadex LH-20 column chromatography, were identified by physicochemical constants and structurally elucidated by spectral methods. Results Four compounds were isolated and identified as: sinensoic acid (1), cerebro-side D (2), poke-weed cerebroside (3), hemisceramide (4). Conclusion Compound 1 is a new compound, others are isolated from the fungus of Ganoderma for the first time.
Two new lanostane-type triterpenoids, ganoderiol A (1) and ganoderiol B (2) were isolated from the fruiting bodies of Ganoderma lucidum, together with known ganodermanontriol (3) and ganodermatriol (4). The compounds were identified as 5∝-lanosta-7, 9(ll)-dien-3β, 24, 25, 26-tetraol (1), 15a, 26, 27-trihydroxy-5α-lanosta-7, 9(11), 24-trien-3-one (2), 24, 25, 26-trihydroxy-5α-lanosta7, 9(1l)-dien-3-one (3) and 5α-lanosta-7, 9(11), 24-trien-3β, 26, 27-triol (4), respectively.
New highly oxidized lanostane-type triterpenoids, ganoderic acid D, E, F, and H and lucidenic acid D, E, and F, were isolated from the gills of Ganoderma lucidum and their structures were elucidated on the basis of spectral evidence.
Two new lanostanoids lucidadiol (1) and lucidal (2), were isolated from an ethanolic extract of Ganoderma lucidum, together with the known compounds ganodermadiol; ganodermenonol; ganoderic acid DM, ergosterol, 22,23-dihydroergosterol; ergosta-7,22-dien-3-one; fungisterol; ergosta-4,6,8(14),22-tetraen-3-one; and ergosterol peroxide. The structures of 1 and 2 were determined based on spectral evidence.
23,24,25,26,27-Pentanorlanost-8-en-3β,22-diol has been isolated from the mycelium of the fungus Verticillium lecanii. Addition of lanosterol to the culture medium did not significantly increase the yields either of the pentanorlanostane metabolites or of ergosterol.
A new alkaloid, sinensine (1), had been isolated from the fruiting bodies of Ganoderma sinense Zhao, Xu et Zhang. Its structure was elucidated on the basis of 1D and 2D spectral analysis. This alkaloid exhibited activity in protecting the injury induced by hydrogen peroxide oxidation on HUVEC, with EC50 value 6.2μmol/L.
Sambucinic acid (5), a C15-trichothecene with a modified strure, has been isolated from cultures of Fusarium sambucinum. The structure is established by spectroscopic data and X-ray diffraction analysis. A hypothetical biogenetic pathway is proposed.
Ten novel components, ganoderic acid, ganoderenic acid and lucidenic acid derivatives, were isolated from the fruiting body of the fungus Ganoderma lucidum. Their structures were elucidated mainly by spectroscopic and chemical methods.
Seven new lanostane-type triterpenes were isolated from the mycelia of Ganoderma lucidum. By spectroscopic analysis, their structures were determined to be 3α,15α,22α-trihydroxylanosta-7,9(11),24-trien-26-oic acid [1], 3β,15β,22β-trihydroxylanosta-7,9(11),24-trien-26-oic acid [2], 3α, 15α-diacetoxy-22α-hydroxylanosta-7,9(11),24-trien-26-oic acid [3], 3β,15α-diacetoxy-22α-hydroxylanosta-7,9(11),24-trien-26-oic acid [4], 22β-acetoxy-3α, 15α-dihydroxylanosta-7,9(11),24-trien-26-oic acid [5], 22β-acetoxy-3β,15α-dihydroxylanosta-7,9(11),24-trien-26-oic acid [6], and 3β,15α-diacetoxylanosta-8,24-dien-26-oic acid [11].
Two new lanostane triterpenes, methyl lucidenate N ( 1) and T-butyl lucidenate B ( 2), were isolated from the fruiting bodies of GANODERMA LUCIDUM together with five known compounds ( 3- 7). The structures of the two new triterpenes were established as methyl 3 β,7 β-dihydroxy-4,4,14 α-trimethyl-11,15-dioxo-5 α-chol-8-en-24-oate ( 1) and T-butyl 7 β,12 β-dihydroxy-4,4,14 α-trimethyl-3,11,15-trioxo-5 α-chol-8-en-24-oate ( 2) by extensive spectroscopic studies and chemical evidence. The effect of the isolated compounds ( 1- 7) on triglyceride (TG) accumulation, an indicator of adipocyte differentiation, during the differentiation of 3T3-L1 preadipocytes was examined. T-Butyl lucidenate B ( 2) reduced the TG accumulation significantly by 72 % at 80 µM compared to the untreated group. Furthermore, compound 2 effectively suppressed the GPDH activity in the cells. Consistent with the decrease in TG accumulation and GPDH activity, compound 2 suppressed the gene expressions of PPAR γ, C/EBP α, and SREBP-1c in a dose-dependent manner during differentiation. Our findings demonstrate that the lanostane triterpenes isolated in this study contribute to the inhibitory effect of the fruiting bodies of G. LUCIDUM on adipocyte differentiation in 3T3-L1 cells.
CHCl(3) extract of the fruiting body of Ganoderma lucidum was found to show inhibitory activity on human aldose reductase in vitro. From the acidic fraction, potent human aldose reductase inhibitors, ganoderic acid C2 (1) and ganoderenic acid A (2), were isolated together with three related compounds. It was found that the free carboxyl group of ganoderic acid C2 and ganoderenic acid A is essential in eliciting the inhibitory activity considering the much lower activity of their methyl esters.
Methyl ganosinensate A (1), ganosinensic acid A (1a), and ganosinensic acid B (2), three new triterpenoids with an unusual four-membered ring skeleton produced by a bond across C-1 to C-11, were isolated from the fruiting body of Ganoderma sinense . Their structures were established on the basis of extensive spectroscopic methods, including 1D and 2D NMR techniques, and methyl ganosinensate A was confirmed by X-ray crystallographic analysis.
Three new lanostane-type triterpenoids having farnesyl hydroquinone moieties, named ganosinensins A-C (1-3), were isolated from the fruiting body of Ganoderma sinense, together with three known lanostane triterpenes, ganodermanontriol, ganoderiol A, and ganoderiol D. The structures of compounds 1-3 were determined by spectroscopic data interpretation.
Three new lanostanoids--ganodermenonol (1), ganodermadiol (2), and ganodermatriol (3) [isolated as its triacetate derivative (3a)]--were isolated from the MeOH extract of Ganoderma lucidum, together with ergosterol and its peroxide. The new compounds were identified as 26-hydroxy-5 alpha-lanosta-7,9(11),24-trien-3-one (1), 5 alpha-lanosta-7,9(11),24-triene-3 beta, 26-diol (2), and 5 alpha-lanosta-7,9(11),24-triene-3 beta, 26,27-triol (3) by their respective spectral data.
A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
A new lanostanoid ester glucoside, 3 alpha-acetoxy-5 alpha-lanosta-8,24-dien-21-oic acid ester beta-d-glucoside (1), and a known steroid, 2 beta,3 alpha,9 alpha-trihydroxy-5 alpha-ergosta-7,22-diene (2), were isolated from the fruit bodies of Ganoderma tsugae and their structures determined by spectroscopic methods. To study the cytotoxicity of 1 and 2, the changes of DNA content in human hepatocytes (Hep 3B) were studied. A sub-G1 cell stage was drastically increased after 24-h incubation with 1 (24 micrograms/mL). Compound 2 (100 micrograms/mL) inhibited the cell cycle progression of Hep 3B cells at the G2/M phase with an IC50 value of about 87.1 micrograms/mL. These results indicate that 1 causes cell death by apoptosis and 2 may possess the activity of cell cycle inhibition.
The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activities of substrates. Whenever 2 or more drugs are administered concurrently, the possibility of drug interactions exists. The ability of a single CYP to metabolise multiple substrates is responsible for a large number of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induction of several human CYPs following long term drug treatment.
The mechanisms of CYP inhibition can be divided into 3 categories: (a) reversible inhibition; (b) quasi-irreversible inhibition; and (c) irreversible inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve only the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are generally irreversible or quasi-irreversible inhibitors. Irreversible and quasi-irreversible inhibition require at least one cycle of the CYP catalytic process.
Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screening tools to predict the potential for in vivo drug interaction. Although it is easy to determine in vitro metabolic drug interactions, the proper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles.
From the viewpoint of drug therapy, to avoid potential drug-drug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-mediated metabolism represents a major route of elimination of many drugs, which can compete for the same CYP enzyme.
The clinical significance of a metabolic drug interaction depends on the magnitude of the change in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the drug. The smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential.
Three new lanostante-type triterpene aldehydes, named lucialdehydes A-C (1-3), were isolated from the fruiting bodies of Ganoderma lucidum, together with ganodermanonol (4), ganodermadiol (5), ganodermanondiol (6), ganodermanontriol (7), ganoderic acid A (8), ganoderic acid B8 (9), and ganoderic acid C1 (10). The structures of the new triterpenes were determined as (24E)-3 beta-hydroxy-5 alpha-lanosta-7,9(11),24-trien-26-al (1), (24E)-3,7-dioxo-5 alpha-lanosta-8,24-dien-26-al (2), and (24E)-3 beta-hydroxy-7-oxo-5 alpha-lanosta-8,24-dien-26-al (3), respectively, by spectroscopic means. The cytotoxicity of the compounds isolated from the ganoderma mushroom was tested in vitro against Lewis lung carcinoma (LLC), T-47D, Sarcoma 180, and Meth-A tumor cell lines. Lucialdehydes B, C (2, 3), ganodermanonol (4) and ganodermanondiol (6) showed cytotoxic effects on tested tumor cells. Of the compounds, lucialdehyde C (3) exhibited the most potent cytotoxicity against LLC, T-47D, Sarcoma 180, and Meth-A tumor cells with ED(50) values of 10.7, 4.7, 7.1, and 3.8 microg/ml, respectively.
Four sterols and 10 triterpenes were isolated from the fruiting bodies of Ganoderma pfeifferi, including the three new triterpenes 3,7,11-trioxo-5alpha-lanosta-8,24-diene-26-al (lucialdehyde D, 1), 5alpha-lanosta-8,24-diene-26-hydroxy-3,7-dione (ganoderone A, 2), and 5alpha-lanosta-8-ene-24,25-epoxy-26-hydroxy-3,7-dione (ganoderone C, 3). The structures of 1-3 were determined on the basis of spectroscopic evidence. Antibacterial, antifungal, and antiviral activity were studied for some of the isolated compounds. Ganoderone A (2), lucialdehyde B (4), and ergosta-7,22-dien-3beta-ol (7) were found to exhibit potent inhibitory activity against herpes simplex virus.
The antiinflammatory properties of triterpenoids and steroids from both Ganoderma lucidum and Ganoderma tsugae were studied. Twelve compounds, including ergosta-7,22-dien-3beta-ol (1), ergosta-7,22-dien-3beta-yl palmitate (2), ergosta-7,22-dien-3-one (3), ergosta-7,22-dien-2beta,3alpha,9alpha-triol (4), 5alpha,8alpha-epidioxyergosta-6,22-dien-3beta-ol (5), ganoderal A (6), ganoderal B (7), ganoderic aldehyde A (8), tsugaric acid A (9), 3-oxo-5alpha-lanosta-8,24-dien-21-oic acid (10), 3alpha-acetoxy-5alpha-lanosta-8,24-dien-21-oic acid ester beta-d-glucoside (11), and tsugaric acid B (12), were assessed in vitro by determining their inhibitory effects on the chemical mediators released from mast cells, neutrophils, and macrophages. Compound 10 showed a significant inhibitory effect on the release of beta-glucuronidase from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB) whereas compound 9 significantly inhibited superoxide anion formation in fMLP/CB-stimulated rat neutrophils. Compound 10 also exhibited a potent inhibitory effect on NO production in lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-stimulated N9 microglial cells. Moreover, compound 9 was also able to protect human keratinocytes against damage induced by ultraviolet B (UV B) light, which indicated 9 could protect keratinocytes from photodamage.
Four new lanostane triterpenes, colossolactone V (1), colossolactone VI (2), colossolactone VII (3), and colossolactone VIII (4), were isolated from the fruiting bodies of the Vietnamese mushroom Ganoderma colossum, together with the known compound colossolactone E (5). The structures of 1- 4 were assigned on the basis of spectroscopic evidence, and their absolute configurations were determined by CD spectroscopy and the Mosher ester method. Compounds 1- 5, as well as two previously isolated compounds [schisanlactone A (6) and colossolactone G (7)] from the same mushroom, were evaluated for inhibition of HIV-1 protease, with IC 50 values for the most potent compounds ranging from 5 to 13 microg/mL.