Revisión

 

Biologically active metabolites of the genus Ganoderma: Three decades of myco–chemistry research

 

Metabolitos biológicamente activos del género Ganoderma: tres décadas de investigación mico–química

 

Ángel Trigos^1,2, Jorge Suárez Medellín^1,3

 

¹ Laboratorio de Alta Tecnología de Xalapa, Universidad Veracruzana. Calle Médicos, 5, Col. Unidad del Bosque. C.P. 91010, Xalapa, Veracruz, México.

² Instituto de Ciencias Básicas, Universidad Veracruzana, Av. Dos Vistas s/n, Carretera Xalapa–Las Trancas, 91000 Xalapa, Veracruz, México.

³ Unidad de Investigación y Desarrollo en Alimentos, Instituto Tecnológico de Veracruz. Av. Miguel A. de Quevedo # 2779 Col. Formando Hogar, C. P. 91680 Veracruz, Veracruz, México.

 

Autor para correspondencia:
Ángel Trigos atrigos@uv.mx

 

Recibido 17 de marzo 2011;
aceptado 17 de noviembre 2011. 

 

Resumen

Desde la antigüedad en la medicina tradicional de oriente, hasta los tiempos modernos, los hongos pertenecientes al género Ganoderma se han utilizado para el tratamiento y la prevención de diversas enfermedades como cáncer, hipertensión y diabetes, entre muchas otras afecciones. Así, a partir de los cuerpos fructíferos, micelio y esporas de diferentes especies de Ganoderma se han aislado más de 140 triterpenoides biológicamente activos y 200 polisacáridos, al igual que proteínas y otros metabolitos diversos. Por lo que el objetivo de este trabajo, es mostrar un panorama general de los principales metabolitos biológicamente activos aislados de los miembros de este género hasta la fecha, aunque sin pretender constituir una revisión exhaustiva, ya que tal cosa sería imposible dado el impresionante dinamismo del tema de investigación.

Palabras clave: compuestos bioactivos, hongos medicinales, metabolitos terapeúticos, polisacáridos, triterpenoides.

 

Abstract

The fungi belonging to the genus Ganoderma have been used since ancient times in Eastern traditional medicine in the treatment and prevention of several diseases such as cancer, hypertension and diabetes, among many other conditions. More than 140 biologically active triterpenoids and 200 polysaccharides, as well as proteins and miscellaneous metabolites have been isolated from the fruiting bodies, mycelium and spores of different species of Ganoderma. The aim of this study is to summarize the main biologically active metabolites isolated from members of this genus to date, yet without pretending to be an exhaustive review, since that would be impossible due the dynamism of the field.

Key words: bioactive compounds, medicinal mushrooms, polysaccharides, therapeutic metabolites, triterpenoids.

 

Introduction

The fungi belonging to the genus Ganoderma (especially G. lucidum), have been used since ancient times in Eastern traditional medicine, until modern days in the treatment and prevention of several diseases such as cancer, hypertension, chronic bronchitis and asthma, among many other conditions,as well as being a key ingredient in the formulation of tonics and sedatives (Lee et al., 2005). More recently, different preparations made from mycelium, fruiting bodies and spores of G. lucidum have been marketed as nutriceuticals or dietary supplements due their antitumor, immunomodulatory and free radical scavenging abilities (Mau et al., 2002; Wachtel–Galor et al., 2004; Wasser et al., 2000). The market for dietary supplements made from G. lucidum has been estimated at about 5 to 6 billion dollars per year, of which 1.6 billion correspond only to its consumption within the United States (Zjawiony, 2004). In addition to G. lucidum, some other species belonging to this genus have be seen to exert diverse salutary effects on human health, including G. tsugae, G. applanatum, G. colossum, G. concinna, G. pfeifferi and G. neo–japonicum (Gan et al., 1998; González et al., 2002; Kleinwátcher et al., 2001; Lee et al., 2005; Mau et al., 2002; Mothana et al., 2000; Zjawiony, 2004).

The genus Ganoderma has been studied from many different points of view, depending on the interests of each research group:

a) As a source of drugs and nutraceuticals (Boh, et al., 2007; Fujita et al., 2005; Han and Yuan, 2005; Joseph et al., 2009; Lindequist et al., 2005; Mau et al., 2002; Mizuno et al., 1995; Suárez–Medellín et al., 2007; Sliva et al., 2003; Tang et al., 2005; Tasaka et al., 1988; Trigos and Suárez–Medellín, 2010; Wachtel–Galor et al., 2004; Wang et al., 2005; Wasser et al., 2000; Yang, 2005).

b) As plant pathogens on crops like oil palm, coconut, rubber, tea, coffee, cocoa and forest trees (Karthikeyan et al., 2009; Paterson, 2007; Zakaria et al., 2005).

c) As a cause of asthma due to the airborne dispersal of spores (Craig and Levetin, 2000).

d) As a source of ligninolytic enzymes with potential applications in pulping, textile dyes, detoxification of polluted water and other biotechnological procedures (Hong and Jung, 2004; Songulashvili et al., 2006; Teerapatsakul et al., 2007; Wang and Ng, 2006).

e) And even as a dietary supplement for farm chickens (Ogbe et al., 2008).

The aim of this study, is to summarize the main biologically active metabolites isolated from members of Ganoderma genus to date, in order to show an overview of the state of art about the mycochemical research of this genus and its potential use as a natural resource.

The text is divided into two main sections. First are presented the biologically active metabolites isolated from Ganoderma lucidum complex, including non–polar metabolites (mostly lanosterol derivatives and related compounds) and polar metabolites (polysaccharides, peptides and proteins). Then are listed the metabolites isolated from other members of this genus, yet without pretending to be an exhaustive review, since that would be impossible due the dynamism of the field.

Biologically active compounds isolated from Ganoderma lucidum complex

The most studied members of Ganodermataceae family are without any doubt, the laccate species belonging to Ganoderma lucidum (Curtis) complex. These fungi, named Reishi in Japan and Ling–zhi in China, have been known since ancient times, and were even mentioned in the famous medical books Shen Nong Ben Cao Jing, (written during the Eastern Han Dynasty) and Ben Cao GangMu (written around 1590 A.C.). Among the wide range of diseases claimed to be successfully treated by G. lucidum are found be: hepatitis, hypercholesterolemia, diabetes, neoplasm, immunodeficiency, leukopenia, atherosclerosis, hemorrhoids, chronic fatigue, insomnia and dizziness caused by neurasthenia, in addition to the previously mentioned cancer, bronchitis and hypertension (Bao et al., 2001; Fujita et al., 2005; Gao et al., 2002; Hajjaj et al., 2005; Lu et al., 2003; Sliva et al., 2003;You and Lin, 2002).

This surprising versatility is due to the large number of bioactive compounds isolated from this fungus. Overall, most of the biologically active metabolites reported for G. lcidum fall into two main groups: those derived from lanosterol (mostly ganoderic acids and related compounds) and polysaccharides (Cole and Schweikert, 2003; Paterson, 2006). However, there are also reports of low molecular weight peptides and proteins (Sripuan et al., 2003; Sun et al., 2004; Wang and Ng, 2006). It has been shown that aqueous extracts of G. lucidum are particularly effective in inhibiting the growth of sarcoma, while non–polar extracts are not, although the latter show strong activity against lipid peroxidation as well as scavenging hydroxyl and superoxide free radicals, among other properties (Jones and Janardhanan, 2000; Lu et al., 2003).

Triterpenoids derived from lanosterol (ganoderic acids and related compounds)

From the non–polar fractions of G. lucidum extracts, more than 130 different triterpenoids have been isolated. All of them are highly oxygenated lanosterol derivatives with pharmacological activity, known as ganoderic acids, ganoderiols, ganolucidic acids, lucidones and lucidenic acids (Cole and Schweikert, 2003).

According to Shiao (2003), among the triterpenoids isolated from this fungus, are predominate pairs of C–3 α/β stereoisomers and C–3/C–15 positional isomers. Ganodermic acids S (1) and R (2) (Figure 1) are a good example of this. The biological activity of the main compounds of this group is summarized in Table 1.

The Isolation of ganoderic acids A (3) and B (4) (Figure 2), was first reported by Kubota et al. (1982) from the chloroform extract of dried fruit bodies of G. lucidum. Since then, the discovery of new lanosterol derivatives in this group of fungi, has carried on with almost no interruption until today.

Toth et al. (1983) showed the occurrence of six polyoxygenated lanostanoids in fruit bodies of G. lucidum, which were named ganoderic acids T (5), V (6), W (7), × (8), Y (9) and Z (10), respectively and Shiao et al. (1988) identified the five compounds from basidiocarps of G. lucidum: Lanosta–7,9(11),24–trien–3β,15α,22β–triacetoxy–26–oic acid (11), lanosta–7,9(11),24–trien–15α–acetoxy–3α–hydroxy–23–oxo–26–oic acid (12), lanosta–7,9(11), 24–trien–3α,15α–diacetoxy–23–oxo–26–oic acid (13), lanosta–7,9 (11), 24–trien–3α–acetoxy–15α–hydroxi–23–oxo–26–oic acid (14), and lanosta–7,9(11),24–trien–3α–acetoxy–15α,22p–dihydroxy–26–oic acid (15) (Figures 1 and 2).

El–Mekkawy et al. (1998) later reported the isolation of 13 metabolites from G. lucidum, which were identified as ganoderic acids α (16), A (3), B (4), C1 (17) and H (18); ganoderiols A (19), B (20) and F (21); ganodermanontriol (22), ergosterol (23), ergosterol peroxide (24), cerevisterol (25) and 3β–5α–dihydroxy–6β–methoxyergosta–7,22–diene (26). This research group found also that ganoderiol F, ganodermanontriol and to a lesser extent ganoderic acids B, C, α and H, ganoderiols A and B, as well as 3β–5α–dihydroxy–6β–methoxyergosta–7,22–diene, showed antiviral activity against HIV–1.

One year later González et al. (1999), reported the isolation of ergosta–7,22–dien–3–one (27); ergosta–5,7–dien–3β–ol,(28) fungisterol (29); ergosterol (23), ergosterol peroxide (24), ergosta–4,6,8(14),22–tetraen–3–one (30), ganodermadiol (31), ganodermenonol (32); ganoderic acid DM (33), lucidadiol (34) and lucidal (35) from G. lucidum.

Another report was made by Min et al. (2000), on the isolation of ganoderic acids γ (36), δ (37), ε (38), ζ (39), η (40) and θ (41),in addition to ganolucidic acids D (42) and C2 (43) from spores of G. lucidum, as well as their citotoxic activity against tumor cell lines Meth–A and LLC.

Wu et al. (2001) then isolated lucidenic acids A, C, N (44), lucidolactone, methyl lucidenate F (45) and ganoderic acid E (46) from dried basidiocarps of G. lucidum. Lucidenic acids A and N, and ganoderic acid E showed citotoxic activity against tumor cell lines Hep G2, Hep G2.2.15 and P–388 and Gao et al. (2002) isolated three lanosterol derivatives from fruit bodies of G. lucidum, known as lucialdehydes A (47), B (48) and C, which was previously named lucidal (35) by González et al., (1999), respectively. This research group also reported the finding of ganodermanonol (32), ganodermadiol (31), ganodermanondiol (49), ganodermanontriol (22), ganoderic acid A (3), ganoderic acid B8 (50) and ganoderic acid C1 (17). Lucialdehydes B and C (or lucidal), as well as ganodermanonol and ganodermanondiol showed citotoxic effects in vitro against Lewis lung carcinoma cells, sarcoma 180, tumor cell lines T–47D and Meth–A (Gao et al., 2002). In a subsequent study performed on antler shaped basidiocarps, these researchers also found lucidimol B (51) and ganodermatriol (52), which showed citotoxicity against Lewis lung carcinoma cells (Gao et al., 2006).

Akisha et al. (2005) reported the occurrence of seven triterpenoids in basidiocarps of G. lucidum, which were identified as: 20(21)–dehydrolucidenic acid A (53), methyl–20(21)–dehydrolucidenate A (54), 20–hydroxilucidenic acid D2 (55), 20–hydroxilucidenic acid F (56), 20–hydroxilucidenic acid E2 (57), 20–hydroxilucidenic acid N (58), and 20–hydroxilucidenic acid P (59).

During that same year Hajjaj et al. (2005) isolated ganoderol A (32) and ganoderol B (31), also known as ganodermanonol and ganodermadiol respectively (González et al., 1999), ganoderal A (60) and ganoderic acid Y (9), from the methanol extract of G. lucidum. These metabolites showed an inhibitory effect on in vitro cholesterol synthesis, by inhibiting the enzyme lanosterol–14α–desmetilase, which transforms 24,25–dihydrolanosterol into cholesterol.

Liu and co–workers (2006a, 2006b), described the inhibitory effect on the enzyme 5α–reductase, induced by lanosterol derivatives such as ganoderic acids TR (61), DM (33), A (3), B (4), C2 (62), D (63), I (64) and 5α–lanosta–7,9 (11),24–trien–15α,26–dihydroxi–3–one (120). These researchers found that compounds with a carbonyl group at C–3 and a carbonyl group α, β unsaturated at C–26, exhibited greater inhibitory effect against that enzyme, which might give them therapeutic and preventive qualities against androgen related diseases such as prostate cancer, male baldness and acne.

Guan and co–workers found two novel triterpenoids in G. lucidum fruiting bodies, identified as 23S–hydroxy–3,7,11,15–tetraoxo–lanost–8,24£–diene–26–oic acid (65) and 12β–acetoxy–3β–hydroxy–7,11,15,23–tetraoxo–lanost–8,20E–diene–26–oic acid (66) (Guan et al., 2008).

Seo and co–workers isolated three steroids and five triterpenoids from the fruiting bodies of G. lucidum, which were identified as ergosterol (23), ergosterol peroxide (24), stella sterol, also known as ergosta–7,22–dien–3β–ol (96), ganoderic acids A (3), C1 (17) and Sz (67), methyl ganoderate A (68) and lucidenic acid A (69). (Seo et al., 2009).

Adams et al. (2010) isolated three new lanostanoids and a benzofuran derivative from the fruiting bodies of G. lucidum, which were named ganoderic acid TR1 (70), ganoderic aldehyde TR (71), 23–hydroxyganoderic acid S (72) and ganofuran B (73).

Weng and co–workers (2010) found two novel sterols with anti–aging effect on yeast, which were identified as ganodermasides A (74) and B (75).

Lee an co–workers (2010a), reported the isolation of four new lanostane triterpenes, known as butyl ganoderate A (76), butyl ganoderate B (77), butyl lucidenate N (78), and butyl lucidenate A (79), from the fruiting bodies of Ganoderma lucidum, which exhibited considerable inhibitory effects on adipogenesis in 3T3–L1 cells. This effect was achieved through down–regulation of SREBP–1c (Lee et al., 2010a and 2010b). The same research team, isolated methyl 7β, 15α–isopropylidenedioxy–3,11,23–trioxo–5α–lanost–8–en–26–oate (80) and n–butyl 12β–acetoxy–3β–hydroxy–7,11,15,23–tetraoxo–5α–lanost–8–en–26–oate (81). Both compounds exhibiting specific anti–acetylcholinesterase activity (Lee et al., 2011).

In addition, Cole and Schweikert (2003), reported several other metabolites isolated from basidiocarps, spores and mycelium of G. lucidum, (like) such as ganoderic acids E (46), F (82), G (83), J (84), K (85), L (86), Ma (87) and U (88), among many others (Figures 1 and 2).

Moreover, all ganoderic acids (G.A) and related compounds are bio–synthesized by the mevalonate/isoprene pathway, which involves the conversion of farnesyl di–phosphate to squalene and then to 2,3 epoxysqualene. The enzyme (S) 3–hydroxy–3–methylglutaryl–CoA reductase (HMGR) catalyzes the first specific step of the isoprenoid biosynthesis, the squalene synthase (SQS) catalyzes the first enzymatic step from the central isoprenoid pathway to the sterol and triterpenoid bio–synthesis and the lanosterol synthase (LS) catalyzes the cyclization of 2,3 epoxysqualene to yield lanosterol, which is the basic skeleton of ganoderic acids and related compounds (Figure 3). Even when it is known that ganoderic acids are synthesized from lanosterol, the final steps of their bio–synthetic pathway include several acylation, oxidation and reduction reactions, which are not yet fully understood. However, it is known that stereoisomers belonging to 3a series are obtained from 3p (Brown, 1998, Shiao, 2003; Xu et al., 2009, 2010).

According to Shiao (2003), the action of ganoderic acids against tumor cell growth might be related to their inhibitory effect on cholesterol synthesis. It is known that several triterpenoids found in G. lucidum inhibit cholesterol bio–synthesis at a postmevalonate step. Mevalonate is an obligatory intermediate step required by normal and cancer cells for cholesterol synthesis, protein prenylation (Ras and G proteins), and DNA synthesis. Deprivation of mevalonate causes cell growth arrest and apoptosis. Since the demands of mevalonate may not be equal between normal and cancer cells, the sensitivity to mevalonate deprivation is greater among the latter, thus causing the observed reduction in tumor cell growth. In addition, G. lucidum triterpenoids inhibit farnesyl protein transferase (FPT) the catalyzed post translational farnesylation of Ras protein. FPT inhibitors have been demonstrated to block Ras dependent cell transformation and therefore represent a potential therapeutic strategy for the treatment of human cancer.

Ganoderma lucidum polysaccharides

Besides the previously discussed triterpenoids, the occurrence of more than 200 polysaccharides has been reported with antitumor and immunomodulatory activity, in the polar extracts of G. lucidum. The main bioactive polysaccharides isolated from this fungus are D–glucanes with β–1–3 and β–1–6 glycosidic bonds. The basic structure of these carbohydrates is conformed by β 1–3–D–glucopyrane and side chains with 1 to 15 units of β 1–6 monoglucosyls with an average molecular weight of 1,050,000 Da (Sone et al., 1985; Yuen and Gohel, 2005).

It is generally accepted that the antitumor activity of Ganoderma polysaccharides is due to their positive effect on the consumer's immune system, rather than direct citotoxicity against cancer cells (Lin and Zhang, 2004).

Among the biological activities reported for the polysaccharides fraction obtained from this fungus the following are to be found: immunomodulation, antihepatotoxicity, free radical scavenging, influence on cell cycle and transduction of cell signals, inhibition of leukemic cell growth, induction of leukemic cells differentiation into monocyte/macrophages, inhibition of blood platelets aggregation, inhibition of the interaction between virus and cell membranes with an increase in the production of IL–2. It was also found that the water–soluble extract of G. lucidum mycelium, and in a dose dependent manner, significantly reduces the incidence and size of tumors induced by azoxymethane and N,N'– dimethylhydrazine in male F344 rat colon cells (Lu et al., 2003; Paterson, 2006; Shiao et al., 2003; Sripuan et al., 2003).

Bao et al., (2001, 2002), reported the occurrence of a D–glucose polysacharide known as PSGL–I–1A, isolated from water–soluble extract of G. lucidum spores, which exerts a stimulating effect on T–lymphocytes. Previously, the same research group found another polysaccharide named PGL, which had a distinct structure with p–D (1–6) bonds, branched with glucosyl side chains linked by p (1–3) and p (1–4) bonds. According to these authors, PGL supresses the proliferation of T–lymphocytes. Hung and co–workers (2008) analyzed the polysaccharide fraction of G. lucidum, and confirmed the presence of 1–3 and 1–6 linkages.

Some other effects attributed to G. lucidum polysaccharides are: antiviral, anti–inflammatory, antioxidant, hypoglycemic, and protection against radiation and DNA damage (Paterson, 2006).

Peptides and proteins

A protein with mitogenic activity named LZ–8 was isolated from G. lucidum mycelium. This polypeptide consists of 110 amino–acid residues with an acetylated amine ending, and has a molecular weight of 12 kDa (Paterson, 2006).

You and Lin (2002) reported the occurrence of a polysaccharide–protein complex known as GLPP that has the ability of neutralizing the damage caused by Reactive Oxygen Species (ROS) in rat macrophages. GLPP has an average molecular weight of 5.13x105 Da and includes the following amino–acids: Asp 8.49, Thr 3.58, Ser 3.93, Glu 5.81, Gly 3.50, Ala 3.84, Cys 1.06, Val 2.68, Met 5.33, Iso–Leu 0.25, Leu 1.5, Phe 1.99, Lys 3.30, His 1.21, Arg 3.94, Pro1.22 (mg/g). The polysaccharide in the complex is made of ramnose, xylose, fructose, galactose and glucose with a molarity of 0.549:3.614:3.167:0.556:6.89, linked by β–glycosidic bonds.

Sripuan et al. (2003) isolated from wild G. lucidum basidiocarps, a α–galactosidase enzyme, able to hydrolyze α–nitrophenyl–α–D–galactopyranoside, as well as melibiose, raffinose and stachyose. In addition to this, a peptideglycan with a hypoglycemic activity known as ganoderan C has been isolated from this fungus. The glycan of this molecule is composed of D–glucose (69.6% of peptideglycan) and D–galactose (2.9 %). Both the backbone and side chains of ganoderan C contained D–glucopyranosyl β 1–3 and β 1–6, linkages as well as a D–galactopyranosil α 1–6 linkage.

Additionally, the occurrence of a low–weight peptide has been proven known as GLP, in the water–soluble extract of this fungus, which is believed to be the main element responsible for G. lucidum antioxidant activity. GLP has shown to play an important role in the inhibition of lipid peroxydation in vivo, due their antioxidant, metal–chelating and free radical scavenging activities (Sun et al., 2004).

Liu and co–workers (2004) reported the isolation of a proteoglycan with a carbohydrate ratio of 10.4:1 from the cultivated mycelia of G. lucidum. This proteoglycan showed antiviral activities against herpes simplex virus types 1 and 2. According to this research group, the proteoglycan inhibits viral replication by interfering with the early events of viral adsorption and entry into target cells (Liu et al., 2004).

Wang and Ng (2006) described the isolation of a ligninolytic enzyme from G. lucidum fresh fruiting bodies, which also exerted a potent inhibitory effect against HIV–1 reverse transcriptase. In addition, there are previous reports of the isolation and characterization of some other laccase isozymes (Ko et al., 2001).

Du et al. (2006) showed that G. lucidum is able to bio–transform inorganic selenium into organic selenium, which is stored in a water–soluble protein. These researchers isolated a selenium–containing protein, belonging to the family of D I N G proteins.

This protein in its native state was identified as a monomer of 36,600 Da and has a remarkable quality in scavenging superoxide and hydroxyl radicals.

Biologically active compounds isolated from other members of Ganoderma genus

G. lucidum is not the only member of the Ganoderma genus able to produce bioactive metabolites. There are several other species of Ganoderma that have proven to be a valuable source of substances with pharmacological potential.

For instance, Lee et al. (2005) reported the occurrence of several substances that are shown to exert potent rat lens aldose reductase inhibition in vitro, in the ethyl acetate extract of G. applanatum (Pers.) basidiocarps. Among those compounds can be found: D–mannitol (89), 2–methoxy fatty acids (90), cerebrosides (91), daucosterol (92), 2,5–dihydroxyacetophenone (93), 2,5 dihydroxybenzoic acid (94) and protocatechualdehyde (95) (Figure 4).

The same fungus, commonly known as "artist's conk", has the sterols 5α–ergost–7–en–3β–ol (29), 5α–ergost–7,22–dien–3β–ol (96), 5,8–epidioxy–5α,8α–ergost–6,22–dien–3β–ol (24) and a lanostanoid (97) that showed remarkable antibiotic activity against gram positive bacteria. Although some polysaccharide have been isolated from the water–soluble extract of G. applanatum, none of them has shown antitumor activity, unlike those isolated from G. lucidum. However, applanoxidic acids A (98), B (99), C, D, E, F, G (100) and H, isolated from a non–polar fraction of this fungus, proved to be effective against skin tumors in mice. On the other hand, it has been reported that G. applanatum extracts have an inhibitory effect on metaloendopeptidase encefalinase EC 3.4.24.11, which might suggest a potential application for this fungus in pain treatment. Furthermore, the occurrence of ergosterol (23), 24ζ–methyl–5a–lanosta–25–one (101), ergosta–7,22–dien–3–one (27), friedelin (102), alnusenone (friedoolean–5–en–3–one) (103), ganoderic acid F (82), ganoderenic acid A (104) and lucidenic acid D1 (105) has been reported for G.applanatum (Boh et al., 2000; Chairul and Hayashi, 1994; Cole and Schweikert, 2003; Gan et al, 1998; Melzig et al, 1996; Zjawiony, 2004).

Wang and Liu (2008), found two new highly oxygenated lanostane type triterpenoids named ganoderic acid AP2 (106) and AP3 (107) from the fruiting bodies of the fungus G. applanatum. In addition, these researchers reported the isolation of ganoderenic acids A (104), B (108), D (109) and G (110) (Figure 17) and Gan et al., (1998) isolated from Ganoderma neojaponicum (Imazeki) the following metabolites: ganoderal A (60), ganodermadiol (31), ergosta–7,22–dien–3β–yl palmitate (111), ergosta–7,22–dien–3–one (27), ergosta–7,22–dien–3β–ol (96), ergosta–4,6,8(14),22–tetraen–3–one (30), and a steroid identified as 2β, 3 ,9 –trihydroxyergosta–7,22–diene (112). Besides, Paterson (2006) reports that two drimane–like sesquiterpenes known as cryptoporic acids H and I, have been isolated from this fungus.

Kleinwätcher et al. (2001) reported the occurrence of seven triterpenoids in G. colossus (Fr.), which were named colosolactones A (113), B (114), C (115), D (116), E (117), F (118) and G (119) (Figure 5). These colosolactones did not show antibiotic activity, but showed moderate citotoxicity against L–929, K–562 and HeLa cells, with IC₅₀ values from 15 to 35 µg/mL. Beside, these substances the 3α–hydroxysteroid dehydrogenase (3α–HSD) inhibited in concentrations comparable to indomethacin as a standard drug, suggesting anti–inflammatory properties.

According to González et al. (2002), 15 compounds have been isolated from G. concinnum (Ryvarden), 12 of them have been previously reported: ganodermanonol (32), ganodermadiol (31), ganoderic acid Y (9), ganoderiol F (21), ganodermatriol (52), ganodermanontriol (22), ganoderiol A (19), ganoderiol B (20), ergosta–7,22–dien–3–one (27), fungisterol (29) and ergosterol peroxide (24). Several of these compounds have proven to exert biological activity in G. lucidum based studies. The other three metabolites were identified as 5α–lanosta–7,9(11),24–trien–3β–hydroxy–26–al (47), 5α–lanosta–7,9(11), 24–trien–15α–26–dihydroxy–3–one (120), and 8α, 9α–epoxy–4,4,14α–trimethyl–3,7,11,15,20–pentaoxo–5α–pregnane (121), and exhibit apoptosis–inducing activity against myeloid leukemia HL–60 cells.

The isolation of ganomycin A (122) and B (123) (Figure 5) has been reported from the European fungus Ganoderma pfeifferi (Bres.). These metabolites showed antibiotic activity against B. subtilis, S. aureus, and Micrococcus flavus, among other bacteria. There were also reports on the isolation of ganodermadiol, and lucidadiol, both showing antiviral activity against influenza virus type A and HSV–1 (Mothana et al., 2000; Zjawiony, 2004).

In addition, Niedermeyer et al. (2005), isolated from G. pfeifferi basidiocarps, the previously known metabolites: ergosta–7,22–dien–3–one (27); ergosta–4,6,8(14),22–tetraen–3–one (30), 5 ,8α–epidioxy–ergosta–6,22–dien–3β–ol (24), lucialdehyde B (48), ganoderol A (32), ganoderol B (31), ganoderal A (60), ergosta–7,22–dien–3β–ol (96) and applanoxidic acids A (98), C and G (100), as well as the new triterpenoids lucialdehyde D (3,7,11–trioxo–5α–lanosta–8,24–dien–26–al) (124), ganoderone A (5α–lanosta–8,24–dien–26–hydroxy–3,7–dione) (125) and ganoderone C (5α–lanosta–8–en–24,25–epoxi–26–hydroxy–3,7,–dione) (126).

As regards to Ganoderma mastoporum (Lév.), Cole et al. (2003), reported the occurrence of ganomastenol A (rel–3 a,8,9 a–trihydroxycadin–4,10(15)–diene) (127), ganomastenol B (rel–3β,8β,9α–trihydroxicadin–4,10(15)–diene) (128), ganomastenol C (rel–3β,8β,9α–trihydroxicadin–10(15)–ene) (129) and ganomastenol D (rel–8β,9α–dihydroxycadin–4–hydroxymethylcadin–4,10(15)–diene) (130).

Meanwhile, Ganoderma australe (Fr.) has triterpenoids with citostatic activity against tumor cells, as ganoderic acids Z (10), Y (9), × (8), W (7), V (6) and T (5), as well as lucialdehydes A (47), B (48) and C (35) (León et al., 2003). From the same fungus Albino–Smania et al. (2007) isolated 5α–ergost–7–en–3β–ol (29), 5α–ergost–7,22–dien–3β–ol (96), 5,8–epidioxy–5α, 8α–ergost–6,22–dien–3β–ol (24), applanoxidic acids A (98), C, F, G (100) and H; as well as australic acid (131) and methyl australate (132) (Figure 5). Both australic acid and methyl australate have activity against bacteria and fungi. In addition to that, Elissetche et al. (2007) isolated two laccase enzymes from G. australe.

During an exhaustive bibliographic review of that genus, Paterson (2006) mentions that from G. lipsiense (Batsch) the following compounds: ergosterol (23); 5α–ergosta–7,22–dien–3β–ol (96), ergosta–7,22–dien–3–one (27), as well as ganoderic acids A (3) and D (63) and their methyl esters have been isolated. The same author, reported on the occurrence of ergosta–7,22–dien–3β–ol (96), ergosta–7,22–dien–3β–yl palmitate (111), 26,27–dihydroxy–lanosta–7,9(11),24–trien–3,16–dione (133), methyl oleate (134) and glyceryl trioleate (135) in G. carnosum (Pat.) (Figure 25). Beside, in G. amboinense (Lam.) has been described the occurence of: ergosta–7,22–dien–3β–ol (96), ergosta–7,22–dien–3β–yl palmitate (111), ergosta–7,22–dien–3β–yl linoleate (136), 2p,3 ,9α–trihydroxy–5α–ergosta–7,22–diene (112), 5α,8α–epidioxy–ergosta–6,9(11),22–trien–3β–ol (24), 2β–methoxyl–3 ,9α–dihydroxy–ergosta–7,22–diene (137) and ganoderic acid AM, also known as 3β–hydroxy–7,11,15,23–tetraoxo–lanosta–8–en–26–oic acid (138) (Figures 5 and 6) (Paterson, 2006). The powder made by grounding the basidiocarps of Ganoderma amboinenese, has shown to excert a preventive effect on acetaminophen–induced acute liver injury (Hsu et al., 2008).

Meanwhile, Shen et al. (2008) reported the isolation and identification of the sterol ergosta–4,6,8(14),22–tetraen–3–one (30), from G. atrum (Zhao).

Niu and co–workers (2006), found three new prenylated phenolic compounds named fornicins A (139), B (140) and C (141) with moderate cytotoxic activity in Hep–2 cells, in the mushroom Ganodermafornicatum (Fr.).

The fungus Ganoderma tsugae (Murr.), which was also used in Eastern traditional medicine just like G. lucidum, has a high antioxidant activity, reducing power, scavenging and chelating abilities and total phenol content. There were reports about the isolation of several lanostanoids with citotoxic activity in vitro from G. tsugae basidiocarps (Figure 6), including tsugaric acids A (142), B (143) and C (144), and tsugarosids A, B and C, in addition to four previously known metabolites: 3β–hydroxy–5α–lanosta–8,24–dien–21–oic acid (145), 3–oxo–5α–lanosta–8,24–dien–21–oic acid (146),ergosta–7,22–dien–3β–ol (96), and 2β,3α,9α–trihydroxy–5α–ergosta–7,22–diene (112). On the other hand, Chen and Chen (2003) reported the isolation of ganoderic acids A (3), B (4), C1 (17), C5 (147), C6 (148), D (63), E (46) and G (83), as well as ganoderenic acid D (109), from G. tsugae fruiting bodies (Chen and Chen, 2003; Mau et al, 2002; Su et al, 2000).

Qiao et al. (2007) isolated two triterpenoids from Ganoderma sinense (Zhao), which were identified as ganolactone B (149) and ganoderiol A triacetate (150). Sato et al. (2009b) reported that five new highly oxygenated lanostane–type triterpenoids known as ganoderic acid GS–1 (151), ganoderic acid GS–2 (152), ganoderic acid GS–3 (153), 20(21)–dehydrolucidenic acid N (154) and 20–hydroxylucidenic acid A (155) were isolated from the fruiting body of G. sinense, together with known compounds including six triterpenoids and three sterols. Among these, ganoderic acids GS–2 and 20(21)–dehydrolucidenic acid N, inhibited the human immunodeficiency virus–1 protease with IC₅₀ values of 20 to 40 µM.

The same research group, also isolated three new lanostane–type triterpenoids having farnesyl hydroquinone moieties, named ganosinensins A (156), B (157) and C (158), from the same fungus (Sato et al., 2009a). Subsequently, Wang et al. (2010) reported on the isolation of three new triterpenoids containing a four–membered ring from the same fungus named methyl ganosinesate A (159), ganosinesic acid A (160) and ganosinesic acid B (161) (Figure 6).

Finally, Welti et al. (2010), reported the isolation of ganoderic acid FWI (162) (Figure 4) from Ganoderma tuberculosum (Murr.). According to these researchers G. tuberculosum extracts might inhibit the growth of cancer cells as well as or even better than those from G. lucidum. Since it has been isolated only from G. tuberculosum, ganoderic acid FWI might be used also as a chemotaxonomic marker.

 

Conclusions

As we can see, during the last thirty years or so, the genus Ganoderma has been extensively researched in order to find new therapeutic metabolites. This research has lead to the isolation of hundreds of new compounds with medicinal value, most of them being either lanosterol derivatives (ganoderic acids and related molecules) or polysaccharides. Among the main biological activities exerted by the lanosterol derivatives are cytotoxicity against several lines of cancer cells, anti–inflammatory, antiviral and hepatoprotective activity, as well as inhibition of 5α–reductase and cholesterol biosynthesis. The polysaccharides on the other hand, are known to enhance the immune system and exert free radical scavenging activity. However, since this genus is one of the largest belonging to the ganodermataceae family, there is still plenty of room for further research.

Even though there is a strong body of evidence suggesting the curative potential of some substances occurring in most members of this genus, it does not necessarily mean that every Ganoderma fungus is always a panacea. First, because those compounds that would exert a positive effect on human health, might actually not be there at all in certain preparations, since the conditions needed for their production are not yet clear (which is by the way, what happens with many secondary metabolites). Second, as Paterson (2006) pointed out, because the toxicology of each particular fungal species has received little attention or none at all. Nevertheless, it is evident that further myco–chemical and pharmacological research will lead to a better understanding (and hence safer use) of these and other related issues.

 

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