Ganopyrone A, a highly rearranged lanostane triterpenoid with antimalarial activity from artificially cultivated fruiting bodies of Ganoderma colossus.

Three previously undescribed highly modified lanostane triterpenoids, ganopyrone A, ganocolossusin I, and ganodermalactone Y, were isolated from the artificially cultivated fruiting bodies of the basidiomycete Ganoderma colossus TBRC-BCC 17711. Ganopyrone A possesses an unprecedented polycyclic carbon skeleton with an α-pyrone ring and C-18/C-23 bond. It showed antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with an IC50 value of 7.8 µM (positive control: dihydroartemisinin, IC50 1.4 nM), while its cytotoxicity (Vero cells) was much weaker (IC50 103 µM).

Antimalarial 9-methoxystrobilurin derivatives from cultures of the basidiomycete Favolaschia minutissima.

Investigation of cultures of the basidiomycete Favolaschia minutissima TBRC-BCC 19434 led to the isolation of two undescribed ß-methoxyacrylate metabolites, 9-methoxystrobilurins R (1) and S (2), and a degraded aldehyde derivative, favodehyde E (3). 9-Methoxystrobilurin derivatives 1 and 2 exhibited significant antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with IC50 values of 0.12 and 0.21 µM, respectively.

Fungal Depsidones Stimulate AKT-Dependent Glucose Uptake in 3T3-L1 Adipocytes.

Enhanced glucose uptake in insulin-sensitive tissues is one of the therapeutic strategies to ameliorate hyperglycemia and maintain glucose homeostasis in type 2 diabetes. This study disclosed the role of fungal depsidones in glucose uptake and the underlying mechanism in 3T3-L1 adipocytes. Depsidones, including nidulin, nornidulin, and unguinol, isolated from Aspergillus unguis, stimulate glucose uptake in adipocytes. Compared to the others, nidulin exhibited an upward trend in glucose uptake. The effect of nidulin was found to be dose- and time-dependent. Nidulin also enhanced insulin- and metformin-stimulated glucose uptake. Upregulation of GLUT4 expression and AKT and AMPK phosphorylation were observed with nidulin treatment. Blockage of AKT, but not AMPK, phosphorylation was largely accompanied by diminished glucose uptake. In agreement, nidulin triggered the translocation of GLUT4 to the plasma membrane. Importantly, nidulin elevated glucose uptake associated with increased AKT phosphorylation in insulin-resistant adipocytes. Taken together, nidulin could stimulate glucose uptake mainly through AKT-dependent GLUT4 translocation, serving as a seed compound in drug discovery for type 2 diabetes.

Antimalarial Lanostane Dimers from Artificially Cultivated Fruiting Bodies of Ganoderma weberianum.

Investigation of cultivated fruiting bodies of Ganoderma weberianum led to the isolation of 11 previously unreported lanostane dimers, ganoweberianones C (3a), D (4a), E (5a), F (6a), G (7a), and H (8a) and isoganoweberianones A (1b), B (2b), D (4b), G (7b), and H (8b). Six new ganodermanontriol derivatives as three pairs of diastereomers (11/12, 13/14, and 15/16) and five new ganoweberianic acids (17-21) were also isolated. A method for semisynthesis of lanostane dimers by condensation of natural lanostanes was established, which was utilized in the structure elucidation and NMR data assignments of the undescribed natural lanostane dimers. Ganoweberianone D (4a) and isoganoweberianone D (4b) showed significant antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with IC50 values of 0.057 and 0.035 µM, respectively, whereas their cytotoxicity to Vero cells was weaker (IC50 8.1 and 19 µM, respectively).

Oudemansin and 9-methoxystrobilurin derivatives with antimalarial activity from cultures of the basidiomycete Favolaschia minutissima: assignments of the absolute configurations of the isoprene-derived units.

Five undescribed polyketide metabolites, oudemansins E (1), M (2), P (3), and Q (4), and 9-methoxystrobilurin I (5), were isolated from cultures of basidiomycete Favolaschia minutissima TBRC-BCC 19434. A γ-lactone derivative (6) of noroudemansin A (8), which was previously reported as a semisynthetic compound, was also isolated. The absolute configuration of the isoprene-derived moiety of the known cometabolite 9-methoxystrobilurin E (9) was determined to be 2'R,6'S by comparison of the experimental and calculated ECD data, which was correlated to the new derivative 1. These compounds exhibited antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain). A putative minor natural product, namely 9-methoxystrobilurin P (13), was prepared by semisynthesis, which exhibited significant antimalarial activity (IC50 0.086 µM).

Pyridylnidulin exerts anti-diabetic properties and improves non-alcoholic fatty liver disease in diet-induced obesity mice.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the metabolic disorders related to the pathophysiology of type 2 diabetes mellitus (T2DM). Therapeutic strategies are focused on the improvement of energy balance and lifestyle modification. Additionally, the derivative of the bioactive fungal metabolite is of interest to provide health benefits, especially in obese and pre-diabetic conditions. In our screening of anti-diabetic compounds from fungal metabolites and semisynthetic derivatives, a depsidone derivative, namely pyridylnidulin (PN), showed potent glucose uptake-inducing activity. The present study aimed to investigate the liver lipid metabolism and anti-diabetic properties of PN in diet-induced obesity mice. Methods: Male C57BL/6 mice were induced obesity and pre-diabetic conditions by dietary intervention with a high-fat diet (HFD) for 6 weeks. These obese mice were orally administered with PN (40 or 120 mg/kg), metformin (150 mg/kg), or vehicle for 4 weeks. Glucose tolerance, plasma adipocytokines, hepatic gene and protein expressions were assessed after treatment. Results: Improved glucose tolerance and reduced fasting blood glucose levels were found in the PN and metformin-treated mice. Additionally, hepatic triglyceride levels were consistent with the histopathological steatosis score regarding hepatocellular hypertrophy in the PN and metformin groups. The levels of plasma adipocytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were reduced in the PN (120 mg/kg) and metformin-treated mice. In addition, hepatic gene expression involved in lipid metabolism, including lipogenic enzymes was significantly reduced in the PN (120 mg/kg) and metformin-treated mice. The increased protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) was also found in PN and metformin-treated mice. Discussion: Considering the increased p-AMPK protein expression levels in PN and metformin-treated mice were revealed as the underlying mechanisms to improve metabolic parameters. These results suggested that PN provided the health benefit to slow the progression of NAFLD and T2DM in obese and pre-diabetic conditions.

Chemical analysis and antitubercular activity evaluation of the dried mycelial powders of the basidiomycete Ganoderma australe TBRC-BCC 22314.

The isolation of lanostane triterpenoids possessing significant anti-tuberculosis (anti-TB) activity from mycelial cultures of the basidiomycete Ganoderma australe strain TBRC-BCC 22314 was previously reported. To demonstrate the potential of the dried mycelial powder for utilization in anti-TB medicinal products, its authentic chemical analysis was performed. Considering the possibility of the changes in the lanostane compositions and anti-TB activity by sterilization, both autoclave treated and non-autoclaved mycelial powder materials were chemically investigated. The study led to the identification of the lanostanes responsible for the activity of the mycelial extract against Mycobacterium tuberculosis H37Ra. The anti-TB activity of the extracts from autoclaved and non-autoclaved mycelial powders were the same (MIC 3.13 µg/mL). However, the analytical results revealed several unique chemical conversions of the lanostanes under the sterilization conditions. The most potent major lanostane, ganodermic acid S (1), was shown to be significantly active also against the extensively drug-resistant (XDR) strains of M. tuberculosis.

Lanostane triterpenoids from artificially cultivated fruiting bodies of Ganoderma cf. mastoporum.

In the quest for bioactive compounds from Ganoderma, artificially cultivated fruiting bodies of Ganoderma cf. mastoporum, strain TBRC-BCC 47851 were chemically investigated. The study led to the isolation of three undescribed lanostane triterpenoids (1-3) together with twelve known compounds. The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data. The new compounds were inactive in the antimalarial and antitubercular activity assays.

Colossolactone J, a highly modified lanostane triterpenoid from a natural fruiting body of Ganoderma colossus.

Colossolactone J (1), an undescribed lanostane triterpenoid was isolated from a natural fruiting body of Ganoderma colossus using silica gel column chromatography and preparative HPLC. Its structure was elucidated on the basis of the spectroscopic method. The absolute configuration was determined by the combination of the modified Mosher's method and detailed NMR data analysis.

Antroxazole A, an oxazole-containing chamigrane dimer from the fungus Antrodiella albocinnamomea with immunosuppressive activity.

Antroxazole A (1), a chamigrane type sesquiterpene dimer containing an oxazole moiety, has been characterized from cultures of the fungus Antrodiella albocinnamomea. The structure with absolute configuration was determined by extensive spectroscopic methods and single crystal X-ray diffraction. A plausible biosynthetic pathway for 1 was proposed. Compound 1 exhibits inhibition specifically against the LPS-induced proliferation of B lymphocyte cells with an IC50 value of 16.3 µM.

[20(22)E]-Lanostane Triterpenes from the Fungus Ganoderma australe.

Twelve new lanostane triterpenoids (1-5, 7-13) were isolated from the fruiting bodies of the fungus Ganoderma australe. The structures of the new compounds were elucidated by extensive 1D and 2D NMR, and HRESIMS spectroscopic analysis. All the triterpenes are featured by 20(22)E configurations which are uncommon in the Ganoderma triterpene family. The absolute configuration of the C-25 of compounds 1, 2, and 6 were determined by the phenylglycine methyl ester (PGME) method. A postulated biosynthetic pathway for compound 1 was discussed. This study opens new insights into the secondary metabolites of the chemically underinvestigated fungus G. australe.

Lanostane triterpenoids from cultivated fruiting bodies of basidiomycete Ganoderma mbrekobenum.

In the quest for medicinally active compounds in mushrooms of the genus Ganoderma, eleven undescribed lanostane triterpenoids, including a novel chlorinated derivative, i.e., (20S,24E)-21-chloro-15ß,20,29-trihydroxy-3,7,11-trioxolanosta-8,24-dien-26-oic acid, were isolated from artificially cultivated fruiting bodies of the basidiomycete Ganoderma mbrekobenum. The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data. The configuration of the C-20 atom in the most abundant 20-hydroxy-lanostane, (20S,24E)-15ß,20,29-trihydroxy-3,7,11-trioxolanosta-8,24-dien-26-oic acid, was established by chemical derivatization, and the absolute configuration of the lanostane skeleton was determined by ECD calculation. Two of the undescribed compounds exhibited moderate antimalarial activity.

Lanostane triterpenoids from cultivated fruiting bodies of Ganoderma sichuanense: Determination of the C-25 absolute configuration of ganoderic acid A and its derivatives using the phenylglycine methyl ester (PGME) method.

Three undescribed lanostane triterpenoids, together with twenty-one known compounds, were isolated from artificially cultivated fruiting bodies of the basidiomycete Ganoderma sichuanense. The absolute configuration at C-25 of ganoderic acid A and its derivatives was determined to be 25R by application of the phenylglycine methyl ester (PGME) method. Among the isolated compounds, ganoderiol F exhibited the most potent activity against Mycobacterium tuberculosis H37Ra with an MIC value of 0.781 µg/ml.

Semisynthetic modifications of antitubercular lanostane triterpenoids from Ganoderma.

Antitubercular lanostane triterpenoids isolated from mycelial cultures of the basidiomycete Ganoderma australe were structurally modified by semisynthesis. One of the synthetic compounds, named GA003 (9), showed more potent activity against Mycobacterium tuberculosis H37Ra than the lead natural lanostane (1). GA003 was also significantly active against the virulent strain (H37Rv) as well as extensively drug-resistant tuberculosis strains.

Acetylenic sesquiterpenoids from cultures of the basidiomycete Stereum cf. hirsutum BCC 26597.

A new acetylenic sesquiterpenoid, stereyne A (1), and its acetonide derivative, stereyne B (2), were isolated from cultures of the basidiomycete Stereum cf. hirsutum BCC 26597. The structures were elucidated by spectroscopic analysis and a chemical correlation. Their absolute configurations were determined by application of the modified Mosher's method. They represent new structural type of sesquiterpenoids from Stereum.

Furan Derivatives and Polyketides from the Fungus Irpex lacteus.

Eight new furan derivatives, irpexins A‒H (1‒8), two new polyketides, irpexins I and J (9 and 10), together with nine known compounds were isolated from the fermentation of Irpex lacteus. The structures and absolute configurations were elucidated on the basis of extensive spectroscopic methods and Mosher ester reaction. All compounds shows no cytotoxicity to human MCF-7 and Hela cancer cell lines at the concentration of 10 µM.

Limonoids from fruiting bodies of the wood-rot basidiomycete Fulvifomes xylocarpicola associated with the mangrove tree Xylocarpus granatum.

Three previously undescribed limonoids, fulvifomins A-C, together with two known compounds, 6-deoxydetigloyl-swietenine acetate and methyl angolensate, were isolated from fruiting bodies of the wood-rot fungus Fulvifomes xylocarpicola (Hymenochaetaceae), growing on the mangrove tree Xylocarpus granatum (Meliaceae). The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data, and X-ray crystallographic analysis (for fulvifomin A). A number of similar limonoids have been isolated from higher plants of the family Meliaceae, including X. granatum. The present study represents a unique evidence that the associated basidiomycete also contains these limonoids. Fulvifomin B exhibited moderate antimalarial and antitubercular activites.

Ganoweberianones A and B, Antimalarial Lanostane Dimers from Cultivated Fruiting Bodies of the Basidiomycete Ganoderma weberianum.

Two lanostane dimers, ganoweberianones A (1) and B (2), together with seven previously undescribed lanostanes, ganoweberianic acids A-G (3-9), and three known compounds (10-12), were isolated from the artificially cultivated fruiting bodies of the basidiomycete Ganoderma weberianum. Ganoweberianone A (1) exhibited significant antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with an IC50 value of 0.050 µM. A method for semisynthesis of 1 by condensation of the corresponding lanostane monomers and acid-catalyzed intramolecular transesterification was demonstrated.

Antimalarial lanostane triterpenoids from cultivated fruiting bodies of the basidiomycete Ganoderma sp.

Ten previously undescribed lanostane-type triterpenoids (1-10), together with 15 known lanostanes, were isolated from artificially cultivated fruiting bodies of the basidiomycete Ganoderma sp. BCC 21329. The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data and by application of the modified Mosher's method. Compounds 1, 3, 5, and 7 showed moderate antimalarial activity (IC50 3.8-7.6 µg ml-1).

Highly Modified Lanostane Triterpenes from the Wood-Rot Basidiomycete Ganoderma colossus: Comparative Chemical Investigations of Natural and Artificially Cultivated Fruiting Bodies and Mycelial Cultures.

The wood-rot basidiomycete Ganoderma colossus has been chemically investigated. Comparative analyses of the natural fruiting body, artificially cultivated fruiting bodies, and mycelial cultures resulted in the isolation, in total, of 13 new highly modified lanostanes, ganocolossusins A-H (1-8) and ganodermalactones T-X (9-13), together with 23 known compounds (14-36). There were significant overlaps of the same compounds among the three different states of the fungal materials. Ganocolossusin D (4) displayed the most potent antimalarial activity against Plasmodium falciparum K1 (multi-drug-resistant strain) with an IC50 value of 2.4 µM, while it was noncytotoxic to Vero cells at 50 µg/mL.