Thelephoric Acid Research Articles

Six new polyphenolic metabolites isolated from the Suillus granulatus and their cytotoxicity against HepG2 cells.

Edible mushrooms are an important source of nutraceuticals and for the discovery of bioactive metabolites as pharmaceuticals. In this work, six new polyphenolic metabolites suillusol A-D (1-4), suillusinoic acid (5), ethyl suillusinoate (6), were isolated from the Suillus granulatus. The structures of new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy, nuclear magnetic resonance data, and single-crystal X-ray diffraction analysis. As far as we know, compound 1 represents an unprecedented type of natural product and compound 3 represents a new type of polyphenol fungal pigment, which may be biosynthetically related to thelephoric acid. The cytotoxicity against HepG2 cells of the new compounds were also evaluated. Compound 2 demonstrate significant inhibitory activity against HepG2 cells with IC50 values of 10.85 μM, surpassing that of positive control cisplatin. Moreover, compound 1 and 3 also exhibited moderate cytotoxic activity with their IC50 values measured at 35.60 and 32.62 μM, respectively. Our results indicate that S. granulatus is a rich source of chemical constituents that may provide new lead compounds for the development of anticancer agents.

Thelephoric acid, p-terphenyl, induces bone-forming activities in pre-osteoblasts

• Thelephoric acid is a p-terphenyl compound isolated from the mushrooms of Polyozellus multiplex. • Thelephoric acid enhances ALP enzymatic activities in pre-osteoblasts. • Thelephoric acid enhances bone matrix mineralization in pre-osteoblasts. • Thelephoric acid enhances nuclear RUNX2 expression and accumulation via Smad1/5/8 phosphorylation. • Thelephoric acid enhances cell adhesion and migration in osteoblast differentiation. • Thelephoric acid is a potentially beneficial compound for prevention and treatment in bone diseases. Polyozellus multiplex , a wild mushroom belonging to Thelephoracea, is distributed in Korea, Japan, and China. Thelephoric acid (Thel), a terphenylquinone found in P. multiplex , reportedly exhibits beneficial effects, including antioxidant, anticancer, and neuroprotective activities. Herein, we extracted Thel from P. multiplex (>95.8% purity) and examined its osteogenic effects on pre-osteoblasts. Thel exerted no cytotoxicity in pre-osteoblasts. Based on alkaline phosphatase staining and activity, Thel promoted osteoblast differentiation and bone matrix mineralization. Biochemical investigations revealed that Thel enhanced nuclear runt-related transcription factor 2 (RUNX2) expression and accumulation via Smad1/5/8 phosphorylation, while exhibiting synergistic activities following cotreatment with bone morphogenetic protein 2 or fibroblast growth factor 2 in pre-osteoblast cultures. Thel increased cell adhesion and migration in differentiating osteoblasts by upregulating matrix metalloproteinase 13 (MMP13). Collectively, these findings indicate that Thel induced osteogenic properties by regulating RUNX2 and MMP13 expression, suggesting that Thel could be further developed to treat bone disorders.

β-Secretase (BACE1) inhibitory and neuroprotective effects of p-terphenyls from Polyozellus multiplex.

Alzheimer's disease (AD), a major neurodegenerative disorder, is associated with the enzymatic reaction of β-secretase (BACE1) on the amyloid precursor protein (APP) for the generation of neurotoxic amyloid-β (Aβ). Therefore, Aβ accumulation and oxidative stress-induced neuronal cell death are the pathogenic hallmarks of AD. In this study, we tried to identify BACE1 inhibitors and neuroprotectants from natural products, in particular, from the Korean mushroom Polyozellus multiplex. Four p-terphenyls were identified from the ethanolic extract of P. multiplex; polyozellin (1), thelephoric acid (2), polyozellic acid (3), and kynapcin-12 (4). Compounds 1-4 effectively inhibited BACE1 activity with a half-maximal inhibitory concentration (IC50) of 3.08, 3.50, 4.78, and 15.79 μM, respectively. Compounds 1-3 reduced the production of neurotoxic Aβ1-42 production in APPswe-N2a cells in a concentration-dependent manner. When HT22 cells were stressed with 5 mM glutamate, compounds 2 and 3 significantly recovered cell viability. It was correlated with their inhibitory properties against glutamate-mediated Ca(2+) influx, intracellular reactive oxygen species (ROS) generation, lipid peroxidation, reduction in Bcl-2 and Bid levels, and enhanced phosphorylation of mitogen-activated protein kinase (MAPK). Thus, P. multiplex and the isolated p-terphenyls might be useful in the development of lead compounds for the prevention of neurodegenerative diseases, especially AD.

A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity.

Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2–33.7 μM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.

Potential Anti-angiogenesis Effects of p-Terphenyl Compounds from Polyozellus multiplex

One novel p-terphenyl compound, polyozellic acid (1), and its acetone adduct (3), along with a known p-terphenyl compound, thelephoric acid (2), were isolated from the mushroom Polyozellus multiplex. Their molecular structures were determined by spectroscopic analysis, X-ray crystallographic analysis, and chemical modification. In some assays related to angiogenesis, compounds 1 and 2 in particular showed inhibitory effects on proliferation, tubule formation, and invasion of human umbilical vein endothelial cells. The quinone moiety within these molecules possibly contributes to their antiangiogenesis activity.

Thelephoric acid의 CYP2J2 효소 활성 저해제 평가

CYP2J2 효소는 간외의 조직에 존재 하는 효소로써, 주로 심혈관계에 발현되어 있다. CYP2J2는 내인성 대사체 및 여러 치료 약물들의 대사에 중요한 작용을 하고 있다. 또한 CYP2J2는 인체의 종양조직이나 종양 세포주에서 과발현되어 있어, 종양 치료를 위한 새로운 표적이 되고 있다. 본 연구에서는 천연물 10종을 대상으로 시토크롬 2J2 동효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 10종의 천연물 중 thelephoric acid는 CYP2J2에 의해 매개되는 에바스틴(<TEX>$IC_{50}=5.32{\mu}M$</TEX>), 아스테미졸(<TEX>$IC_{50}3.23{\mu}M$</TEX>) 및 터페나딘(<TEX>$IC_{50}=3.27{\mu}M$</TEX>) 대사를 강력하게 저해하였다. 향후, 이 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다. Cytochrome P450 2J2 (CYP2J2) is an enzyme mainly found in human extrahepatic tissues, with predominant expression in the cardiovascular system. CYP2J2 plays important roles in the metabolism of endogenous metabolites and therapeutic drugs, such as arachidonic acid, astemizole, ebastine, and terfenadine. CYP2J2 is also overexpressed in human cancer tissues and cancer cell lines and may represent a potential target for therapy of human cancers. In this study, 10 natural products obtained from plants and microorganisms were screened as potential CYP2J2 inhibitors. Among them, thelephoric acid showed strong inhibition of astemizole O-demethylation activity (<TEX>$IC_{50}=3.23{\mu}M$</TEX>) in a dose-dependent manner. Evaluation of the substrate dependency of the inhibitory activity of thelephoric acid showed that it strongly inhibited CYP2J2-mediated ebastine hydroxylation (<TEX>$IC_{50}=5.32{\mu}M$</TEX>) and terfenadine hydroxylation (<TEX>$IC_{50}=3.27{\mu}M$</TEX>) in a substrate nondependent manner. The present data suggest that this compound might be a potential candidate for further evaluation for anticancer activity.

Piceirhiza nigra, an ectomycorrhiza on Picea abies formed by a species of Thelephoraceae

summaryEctomycorrhizas of Picea abies (L.) Karst., previously described as Piceirhiza nigra, are shown to be formed by a member of the Thelephoraceae by virtue of the presence of thelephoric acid.

Pilzfarbstoffe, 54 [1] / Fungal Pigments, 54 [1

Abstract Fruitbodies of the basidiomycete Boletopsis leucomelaena contain the leuco-peracetates of thelephoric acid and cycloleucomelone (3 and 4, respectively). The latter compound is accom­panied by a series of analogues, containing five, four, and three acetyl residues. The properties of Akagi’s “leucomelone” (1) and “protoleucomelone” (2) correspond to those of cycloleucomelone (7) and its leuco-peracetate 4.

Pigments of fungi (Macromycetes).

The Macromycetes exhibit a great variety of colours and colour changes which have traditionally been used by mycologists as taxonomic characters. The scientific bases of these phenomena have attracted the attention of organic chemists for over a century, the beginnings of chemical investigations of the pigments of mushrooms and toadstools being readily identified with the works of Bachmann (57, 58), Stahlschmidt (591, 592), Thörner (653, 654), Zellner (726), and Zopf (732). Much of the chemistry which emerged from these pioneering studies has been reviewed in the older literature (112, 174, 363, 424, 519). The elucidation of the structures of polyporic acid and atromentin by Kögl (423, 425, 426, 431, 433) represented a significant advance in this field but later work by this author, principally on ‘boletol’ (427, 428), ‘muscarufin’ (429) and the structure of thelephoric acid (430), has unfortunately not withstood the test of time and meanwhile has caused considerable confusion.

Constituents of the higher fungi Part XV. 3-(3,4-Dihydroxyphenyl)-2,7,8-trihydroxydibenzofuran-1,4-dione, a precursor of thelephoric acid from the fungus Suillus grevillei(klotsch) sing. [Boletus elegans(schum. per Fries)

3-(3,4-Dihydroxyphenyl)-2,7,8-trihydroxydibenzofuran-1,4-dione has been isolated from the fungus Suillus grevillei. Solutions of this compound are unstable and yield thelephoric acid.

ChemInform Abstract: CONSTITUENTS OF THE HIGHER FUNGI PART 14, 3′,4′,4‐TRIHYDROXYPULVINONE, THELEPHORIC ACID, AND NOVEL PYRANDIONE AND FURANONE PIGMENTS FROM SUILLUS GREVILLEI (KLOTSCH) SING. (BOLETUS ELEGANS (SCHUM. PER FRIES))

Chemischer InformationsdienstVolume 4, Issue 49 Natural Products ChemInform Abstract: CONSTITUENTS OF THE HIGHER FUNGI PART 14, 3′,4′,4-TRIHYDROXYPULVINONE, THELEPHORIC ACID, AND NOVEL PYRANDIONE AND FURANONE PIGMENTS FROM SUILLUS GREVILLEI (KLOTSCH) SING. (BOLETUS ELEGANS (SCHUM. PER FRIES)) RAYMOND L. EDWARDS, RAYMOND L. EDWARDSSearch for more papers by this authorMELVYN GILL, MELVYN GILLSearch for more papers by this author RAYMOND L. EDWARDS, RAYMOND L. EDWARDSSearch for more papers by this authorMELVYN GILL, MELVYN GILLSearch for more papers by this author First published: December 4, 1973 https://doi.org/10.1002/chin.197349472AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume4, Issue49December 4, 1973 RelatedInformation

Constituents of the higher fungi. Part XIV. 3′,4′,4-Trihydroxypulvinone, thelephoric acid, and novel pyrandione and furanone pigments from Suillus grevillei(Klotsch) Sing. [Boletus elegans(Schum. per Fries)

Eight crystalline pigments have been isolated from the fungus Suillus grevillei. 3′,4′,4-Trihydroxypulvinone, a novel pyrandione, and a novel furanone are described, and thelephoric acid is identified as the cap skin pigment of Suillus grevillei var. badius

A new species of Phellodon possessing clamp connections

The finding of clamps throughout the tissues in Phellodon fibulatus sp. nov. raises a question as to the recognition of the family Bankeraceae, characterized mainly by hyaline echinulate spores and a distinctive odor when dried. Grand and Moore have shown that the ornamentation on the spores of Phellodon is the same as in Hydnellum and Hydnum, and Brady reports the presence of the thelephoric acid in the same genera. This leaves hyaline spores as the only significant difference between Hydnellum and Phellodon. Odor of the dried specimens is considered to be of doubtful value as a family character. It is concluded that the family Bankeraceae is superfluous, and its genera are referred to the Hydnaceae.

Occurrence of Atromentin and Thelephoric Acid in Cultures of Clitocybe Subilludens

Atromentin was found to be present in both 30- and 45-day-old cultures of Clitocybe subilludens Murr., whereas thelephoric acid was present in the 30-, 45-, and 60-day-old cultures. These cultures were grown on 6% malt extract agar under continuous light conditions at 29° for 15, 30, 45, and 60 days. Cultures grown in the absence of light failed to produce detectable quantities of either terphenylquinone. Examination of all cultures for diphenyl-substituted tetronic acids failed to demonstrate detectable amounts. It is postulated from these observations that atromentin may act as a precursor for thelephoric acid, since the disappearance of the former coincides with the appearance of the latter terphenyl-quinone.

Chemical Studies in the Genus Lobaria and the Occurrence of a New Tridepside, 4-O-Methylgyrophoric Acid

Chemical Studies in the Genus Lobaria and the Occurrence of a New Tridepside, 4-O-Methylgyrophoric Acid

Qualitation and quantitation of some terphenylquinones

Microchemical and photochemical procedures which would permit rapid, sensitive detection of atromentin, aurantiacin, and thelephoric acid were examined. Photochemically induced fluorescence and chromophore formation with a ceric ammonium sulfate (CAS) reagent were useful for this purpose, especially when the terphenyl-quinones were adsorbed on polyamide powder. Quantitation of atromentin was possible with a CAS procedure, and all three of the terphenylquinones could be quanti-tated with pyridine-water (Py–W) and combined Py–W–CAS procedures. The relative sensitivities for the quantitative methods for atromentin were CAS > Py–W–CAS > Py–W. The procedures permitted the determination of atromentin and aurantiacin in concentrations of 2 to 120 mcg./ml. and 4 to 120 mcg./ml., respectively, and of thelephoric acid in concentrations of 2 to 40 mcg./ml. Precise standardization of analytical conditions was critical.

A New Synthesis of Thelephoric Acid.

A New Synthesis of Thelephoric Acid.

Fungus pigments—XII : The structure and synthesis of thelephoric acid

Degradative and spectroscopical evidence, as well as biogenetic considerations led to the conclusion that thelephoric acid is 2,3,8,9-tetrahydroxybenzobis[1,2-b,4,5-b′]benzofuran-6,12-quinone(VI). This view was confirmed by synthesis, involving condensation of chloranil with two molecules of 3,4-dimethoxyphenol and subsequent demethylation.

The structure of thelephoric acid

The structure of thelephoric acid

THELEPHORIC ACID

The electronic and infrared absorption spectra of thelephoric acid and its leucoacetate indicate that the structure at present accepted for the pigment is incorrect. It is suggested from an interpretation of these spectra, together with a re-evaluation of the reported properties of thelephoric acid and its derivatives, that the substance may be a hydroxylated terphenyl containing internal quinhydrone and benzofuran systems (e.g. (V)).