Styrylpyrone-Class Compounds from Medicinal Fungi Phellinus and Inonotus Spp., and Their Medicinal Importance
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The Journal of Antibiotics (2011) 64, 349–359 & 2011 Japan Antibiotics Research Association All rights reserved 0021-8820/11 $32.00 www.nature.com/ja REVIEW ARTICLE Styrylpyrone-class compounds from medicinal fungi Phellinus and Inonotus spp., and their medicinal importance In-Kyoung Lee and Bong-Sik Yun Members of the genera Phellinus and Inonotus, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus are well-known medicinal fungi (mushrooms) and have been used in treatment of cancer, diabetes, bacterial and viral infections and ulcer. Adverse effects of these medicinal mushrooms have not yet been reported, indicating the safe nature of these mushrooms. Polysaccharides, particularly b-glucan, are considered the compounds responsible for the biological activity of medicinal mushrooms. However, there is only a limited amount of evidence to indicate that polysaccharides are in fact responsible for the biological effects of these medicinal mushrooms. Recently, many research groups have begun identification of active low-MW compounds in medicinal mushrooms, with a focus on the yellow polyphenol pigments, which are composed of a styrylpyrone class of compounds. Interestingly, a representative group of medicinal fungi, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus were shown to produce a large and diverse range of styrylpyrone-type polyphenol pigments that exhibited various biological activities, including anti-oxidative, anti-inflammatory, cytotoxic, anti-platelet aggregation, anti-diabetic, anti-dementia and anti-viral effects. Styrylpyrone pigments in mushrooms are thought to have a role similar to that of flavonoids in plants. The unique and unprecedented carbon skeleton of fused styrylpyrone might be an attractive molecular scaffold for pharmacological applications. In this review, the structural diversity, biological effects and biogenesis of styrylpyrone-class polyphenols from medicinal fungi are described. The Journal of Antibiotics (2011) 64, 349–359; doi:10.1038/ja.2011.2; published online 9 February 2011 Keywords: biological activity; Inonotus; medicinal mushrooms; Phellinus;styrylpyrone INTRODUCTION have been developed and used extensively as anti-cancer drugs in Asia. Mushrooms are ubiquitous in nature and are a good source of food Although an overwhelming number of reports have been published on with high nutritional attributes. Some mushrooms have been shown the importance of polysaccharides as immunomodulating agents, not to be physiologically beneficial to humans and to produce various all of the curative properties found in these medicinal fungi could be classes of structurally unique and biologically active metabolites that fully accounted for.11–15 exhibit significant anti-microbial, anti-tumor and anti-viral activ- Recently, these medicinal fungi have been reported to produce a ities.1–5 Members of the genera Phellinus and Inonotus, including variety of yellow polyphenol pigments, known as styrylpyrones, which P. linteus, P. ribis, P. igniarius, I. obliquus,andI. xeranticus,have have shown significant biological effects, such as anti-oxidative, been used as traditional medicines for treatment of gastrointestinal anti-cancer, anti-platelet, anti-diabetic, anti-inflammatory and anti- cancer, cardiovascular disease, tuberculosis, liver or heart disease, viral activities. Since the first isolation of hispidin (1) as a naturally fester, bellyache, blood gonorrhea, stomach ailment and diabetes.6 occurring styrylpyrone from Inonotus hispidus (formerly Polyporus However, despite increased usage, their pharmacological actions hispidus) in 1889, a number of other styrylpyrone metabolites from have not been well established. Polysaccharides, particularly b-glucan, Phellinus and Inonotus have been discovered. Styrylpyrone pigments are believed to be responsible for the biological activity of medicinal are common constituents of fungi, mainly those belonging to the mushrooms, and a number of polysaccharides and protein-bound Hymenochaetaceae family, including Phellinus and Inonotus.16 They polysaccharides have been used clinically for treatment of cancer. also exist in primitive angiosperm families, including Piperaceae, Examples include the polysaccharopeptide Krestin from Coriolus Lauraceae, Annonaceae, Ranuculaceae and Zingiberaceae, where they versicolor,7 Mesima from P. linteus,8 Lentinan from Lentinus edodes,9 have an important role in defense against mechanical wounding and Schizophylan from Schizophyllum commune.10 These polysaccharides or microbial attack, and show potent biological activities, including Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Jeonbuk, Korea Correspondence: Dr B-S Yun, Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, 194-5 Ma-Dong, Iksan, Jeonbuk 570-752, Korea. E-mail: [email protected] Received 30 July 2010; revised 21 December 2011; accepted 6 January 2011; published online 9 February 2011 Styrylpyrones from medicinal fungi and their medicinal importance I-K Lee and B-S Yun 350 anti-cancer and sedative effects.17,18 Biogenesis of fungal styrylpyrones (3), hypholomine B (5) and 1,1-distyrylpyrylethan (10), existed in and their intrinsic role in fungi, like the phenylpropanoid derivatives cultured broths of I. xeranticus and P. linteus.34 These compounds of plants, which have important ecological and physiological roles, exhibited significant free radical scavenging activity. Hispidin (1)and have attracted much attention. Styrylpyrones are regarded as pheny- hypholomine B (5) were the most abundant metabolites and were lalanine (Phe)-derived fungal metabolites with a variety of functions, found to be responsible for the anti-oxidative activity of the crude including defense, pigmentation and signaling molecules. extract. Caffeic acid (11), a precursor of hispidin biosynthesis, was Classification of fungal metabolites based on their putative bio- found to be highly accumulated in culture broths containing small synthesis was first reported by Turner and Aldridge.19 Subsequently, in amounts of hispidin (1) and hypholomine B (5). The reason for this is 1987, Gill and Steglich20 conducted a comprehensive study of styr- still not clear, but may be due to weak activity of the enzymes ylpyrones isolated from fungi belonging to the macromycetes. Gill associated with hispidin biosynthesis. Although biosynthesis of continued this work, and reported on a variety of fungal pigments dimeric hispidins from two monomers via oxidative coupling by from 1986 to 2001.21–23 They were classified as styrylpyrones accord- lignolytic enzymes, laccase and peroxidase, has been proposed, the ing to their biogenesis by Dewick, who introduced styrylpyrone and details of this process remain unknown. In preliminary experiments, kavapyrone derived from the plant Piper methysticum.18 Styrylpyrones we attempted enzymatic synthesis of the hispidin dimer from hispidin were not discovered until 30 years after hispidin (1)andseveralofits (1) using commercially available horseradish peroxidase, resulting in dimers were isolated in the mid 1970 s. production of a hispidin dimer, 3,14¢-bihispidinyl (3).35 whereas the This review includes a discussion of styrylpyrone metabolites other dimers including hypholomine B (5) and 1,1-distyrylpyrylethan isolated from Phellinus and Inonotus during the past 10 years, and a (10) were not detected. This result revealed the dominance of the presentation on recent progress in isolation, structural diversity, coupling modes forming the covalent bond at C-3 and C-14¢ of two biological activities and biosynthesis of styrylpyrones from these units of hispidin (1), and indicated that additional catalysts or medicinal fungi. substrates are needed for synthesis of other hispidin dimers. This result also suggests that hispidin redox potentials and different types of STRUCTURAL DIVERSITY OF STYRYLPYRONES peroxidase are sufficient for generation of the biosynthetic diversity of Hispidin (1) and bisnoryangonin (2) may be the best-known exam- styrylpyrones and production of many of its derivatives that have not ples of styrylpyrones. Compound 1 was first isolated from I. hispidus yet been identified. by Zopf in 1889, but was first identified as 6-(3¢,4¢-dihydroxystyryl)-4- Natural anti-inflammatory and anti-arthritic agents against 3a- hydroxy-2-pyrone by Edwards in 1961 and by Bu’Lock in 1962.20 hydroxysteroid dehydrogenase, cyclooxygenase and xanthine oxidase Labeling experiments in cultures of I. hispidus and Phaeolus schwei- were isolated from the ethanolic extract of the fruiting body of nitzii have demonstrated that the styryl group is derived from Phe via Inonotus sp. and identified as hispidin (1), isohispidin (tautomeric cinnamic acid, p-coumaric acid and caffeoyl-CoA pathways, whereas g-pyrone, 12), 4-(3,4-dihydroxyphenyl)-but-3-en-2-one (13), inonotic the pyrone ring is derived from acetate.24–26 In addition, compound 1 acid methylester (14) and inotilone (15).36 Isohispidin (12) co-occurs was shown to be biosynthesized by hydroxylase, which catalyzes as a minor compound, together with hispidin (1), suggesting that hydroxylation of compound 2. Compounds 1 and 2 were isolated hispidin is a more stable structure than isohispidin (12). These from fungi belonging to the genera Gymnopilus, Hypholoma and metabolites (1, 12–15) share the same biosynthetic origin as polyke- Pholiota in the Agaricales, and genera belonging to the family tides derived