摘要
天然小分子化合物种类繁多、数量巨大,不但具有化学调节、信号载体、化学防御等多种生理作用,而且是药物开发的重要资源。组合生物合成等技术可以定向合成与创造新的天然产物衍生物,但作为药物发现的工具还有待进一步发展和完善。天然产物的多样性是任何科学家无法想象的,仍然是新药研发的重要先导化合物。
食药用大型真菌是产生新结构与具有活性天然小分子化合物的重要生物类群。近年来,越来越多的食药用真菌可以通过液体发酵或固体发酵方式来大量培养,而且它们发酵产物的营养价值与化学成分含量远高于天然或人工栽培的子实体或菌核。因此,研究食药用真菌发酵产生的天然小分子化合物的多样性与活性已成为天然产物化学家与真菌学家共同关注的重要领域。
本文以国外引进的巴西革耳,野生分离的珊瑚菌、杨黄菌、花脸香蘑、虫草菌、羊肚菌、安络小皮伞、松乳菇、干巴菌、鳞伞和常规栽培的大杯伞、白色茶树菇、金针菇、牛舌菌、猴头菌、长根小奥德蘑、榆黄蘑、杏鲍菇等20种食药用大型真菌为材料,利用高效液相色谱、薄层层析色谱比较它们液体培养与固体培养的粗提物化学成分,并进行生物活性测定。珊瑚菌的甲醇提取物产量较高。MTT测定表明大部分食药用真菌的甲醇提取物具有不同程度的细胞毒活性,猴头菌与巴西革耳甲醇提取物的作用较强;鳞伞甲醇提取物的抗细菌和抗真菌活性较强;牛舌菌和杨黄菌的甲醇提取物具有抑制弹性蛋白酶活性的作用。选取珊瑚菌、巴西革耳、鳞伞、杨黄菌和猴头菌为菌种,对它们液体或固体发酵的化学成分进行系统的分离。利用核磁共振波谱、质谱、紫外光谱、红外光谱、旋光、园二色谱和X射线单晶衍射及各种化学反应对化合物的结构进行了鉴定。共分离鉴定了55个化合物,其中25个为新化合物。并初步研究了部分化合物的活性及作用机理。
从珊瑚菌固体发酵产物中分离并鉴定了22个化合物,化合物类型涉及倍半萜、芳香类、腺苷、大环内酯和吡喃酮化合物,其中有7个新倍半萜(2个为新骨架,4个为Protoilludane型骨架)、1个新倍半萜二聚体、1个新对甲基苯戊二醇衍生物和1个新大环内酯共10个新化合物。首次用X射线单晶衍射解析了新骨架倍半萜、tsugicoline C、腺苷和苯基丁烯内酯的结构。利用高效液相色谱技术研究了珊瑚菌液体发酵主要倍半萜的生物转化,探讨了珊瑚菌倍半萜生物合成的可能途径。
从巴西革耳固体发酵产物中分离并鉴定了10个化合物,包括prenylhydroquinone、聚酮、生物碱和甾醇等结构类型,其中6个为新化合物。MTT试验表明化合物YB110有较好的细胞毒活性,对HeLa细胞的IC_(50)为38.9μM,细胞成活率与细胞周期分析表明YB110具有引起HeLa细胞凋亡的作用。
从杨黄菌固体发酵产物中分离并鉴定了6个化合物:5个是脱落酸类似物的倍半萜,其中2个为新化合物;另外1个化合物为腺苷。
从鳞伞液体发酵产物中分离并鉴定了7个化合物:6个为具有drimane型骨架的倍半萜,其中3个为新化合物,分离的已知化合物agrocybolacton具有抗细菌活性;另外1个是具有较强抗真菌等活性的三炔类化合物,并首次用X射线单晶衍射晶体数据解析其结构。
从猴头菌液体静置发酵产物分离并鉴定了10个化合物,其中4个为新化合物。化合物类型有芳香类、吡喃酮、二萜和聚酮等。主要的化学成分为具有较强抗肿瘤活性和促进神经生长因子产生的已知化合物erinacine P。
本文研究表明,通过发酵,食药用大型真菌可以产生结构类型与生物活性多样的天然产物,分离到的化合物是新药开发与生物学功能研究的重要资源。另外,不同食药用真菌的天然产物具有一定的结构类型,可作为菌种鉴别与分类的化学依据。
Large quantity of natural products with different structure types have not only been focused on the study of functional molecules for the organism in the fields of chemical defense,chemical regulation and signal transduction,but also played a vital role in the discovery of new pharmacy.Many natural product derivatives with specific structure can be produced through combinatorial chemistry and other biotechnologies, but they need to be improved for the discovery of new pharmacy.The diversity of natural products were hard to be imagined and designed by any scientists.The natural products were still important resources of lead compounds of new pharmacy.
Edible and medicinal macrofungi can produced abundant natural products with many kinds of bioactivity.Recent years,more and more edible and medicinal macrofungi can be cultured by liquid and solid fermentation.Moreover,it was proved that the nutritional value and chemical component of fermentation product of these macrofungi were higher and more abundant than their fruit body or sclerotium.So,the diversity and bioactivity of natural product from edible and medicinal macrofungi by fermentation attracted more and more attention of natural products chemist and mycologist.
In this study,the component and bioactivity of organic extract from 18 edible and medicinal macrofungi including 1 strains introduced from Brazi(Lentinus striguellus,), 10 strains isolated from the wild(Clavicorona pyxidata,Fistulina hepatica,Phellinus vanini,Lepista sordida,Morchella esculenta,Marasmius androsaceus,Lactarius deliciosus,Thelephora ganbajum,Cordyceps sinensis and Agrocybe sp.,) and 5 strains that have been extensively cultivated(Agrocybe chaxinggu,Clitocybe illudens, FlammuLina veLatipes,Hericium erinaceus,Oudemansiella radicata,Pleurotus citrinopileatus,Pleurotus eryngii) were explored.The results showed that the methanol extract from Clavicorona pyxidata was more abundant than others.MTT assays indicated that the methanol extract from Hericium erinaceus and Lentinus striguellus have stronger cytotoxity against HeLa cells than other extracts.The methanol extracts from Agrocybe sp had the bioactivity of antibacteria and anti-candida.The methanol extracts from Phellinus vanini and Fistulina hepatica had the bioactivity of inhibition on elastase.So,the strains Clavicorona pyxidata,Phellinus sp.,Agrocybe sp.,Hericium erinaceus and Lentinus striguellus were selected for further investigation of natural products from these strains by liquid or solid fermentation.In consequence,55 natural products,whose structure were elucidated by NMR spectroscopic data,mass-spectrometric,UV,IR,rotational,circular diophrism, chemical reactions and X-ray single crystal diffraction,were isolated from these selective strains.25 natural products of these compounds were new.
Twenty-two compounds were isolated and eluciated from the strain Clavicorona pyxidata,including sesquiterpenes、aromatic derivatives、macrolide、pyrone、polyketide and adenosine.There were ten new compounds including two sesquiterpenes with novel backbone,named as clavicoronane-type,four new protoilludane-type sesquiterpenes,one new tsugicoline L-type sesquiterpenes,one new sesquiterpene dimer,one new methylphenyl-pentanediol derivatives and one new macrolide.The crystallographic data of the compounds phenylbutenolide derivative,adenosine,tsugicoline C,and one novel clavicoronane-type sesquiterpene obtained from the X-ray single crystal diffraction were first reported and have been deposited with the Cambridge Crysatallographic Data Center.Additionally,the transformation of major sesquiterpenes in the liquid fermentation of Clavicorona pyxidata were explored by the method of HPLC and TLC.The biosynthesis pathway of major sesquiterpenes of Clavicorona pyxidata was putated.
Ten compounds were isolated and identified from the strain Lentinus striguellus, including seven prenylhydroquinones,one sterols,one polyketide and one alkaloid. There were six new compounds including four Prenylhydroquinones(lentinols A-D), striguellone A and one alkaloid.Striguellone A showed cytotoxicity against HeLa cells by MTT assay and was found to be an activator of apoptosis,assessed by morphological observation and cell cycle analysis by the flow cytometer.
Five abscisic acid-type sesquiterpenes(two of these compounds were new) and adenosine were isolated and identified from the strain Phellinus vanini.
Seven compounds were isolated and identified from the strain Agrocybe sp. including the five drimane-type sesquiterpenes,one norsesquiterpene and one known compound agrocybin,a polyacetylene with the bioactivities of cytotoxic, immunosuppressive,trypanocidal and antifungal.Two drimane-type sesquiterpenes and the norsesquiterpene were new.
Ten natural products(four of them were new) were isolated and identified from the strain Hericium erinaceus,including aromatic derivatives,pyrone derivatives, polyketide and diterpenoid.The major component was the known diterpenoid compound erinacine P which was nerve growrh factor and has the bioability of cytotxity.
In a conclusion,our works indicated that edible and medicinal macrofungi could produced abundant natural products with many kinds of structure type and had diverse bioactivities including antimicrobial and antitumor through fermentation. Moreover,the speciality of these compounds from these different strains will be chemical markers for classification.
引文
[1]Fu H,Chen S,Chen R,Ding W,Kuo Huang L,Huang R.Identification of oxalic acid and tartaric acid as major persistent pain-inducing toxins in the stinging hairs of the nettle,Urtica thunbergiana[J].Ann Bot(Lond),2006,98:57-65.
[2]Sarin R,Khandelwal S.Insecticidal activity of pyrethrins from flowers of Wedelia calendulacea Less[J].Recent Progress in Medicinal Plants,2006,12:381-384.
[3]Mace ME,Stipanovic RD,Bell AA.Toxicity of cotton phytoalexins to zoopathogenic fungi [J].Natural Toxins,1993,1:294-295.
[4]Ogunil.Dehydroipomeamarone as an Intermediate in the Biosynthesis of Ipomeamarone,a Phytoalexin from Sweet Potato Root Infected with Ceratocystis fimbriata[J].Plant Physiology,1974,53:649-652.
[5]Conway B-AD,Venu V,Speert DP.biofilm formation and acyl homoserine lactone production in the Burkholderia cepacia complex[J].Journal of Bacteriology,2002,184:5678-5685.
[6]Deziel E,Lepine F,Milot S,He J,Mindrinos MN,Tompkins RG,et al.Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines(HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication[J].Proceedings of the National Academy of Sciences of the United States of America,2004,101:1339-1344.
[7]Wang LH,He Y,Gao Y,Wu JE,Dong YH,He C,et al.A bacterial cell-cell communication signal with cross-kingdom structural analogues[J].Molecular Microbiology,2004,51:903-912.
[8]Holden MTG,Chhabra SR,De Nys R,Stead P,Bainton N J,Hill P J,et al.Quorum-sensing cross talk:isolation and chemical characterization of cyclic dipeptides from Pseudomonas aeruginosa and other Gram-negative bacteria[J].Molecular Microbiology,1999,33:1254-1266.
[9]Sattelle DB,Sepulveda MI,Shinozaki H,Ishida M.Actions of acromelic acid on nervous system L-glutamate receptors[J].Archives of Insect Biochemistry and Physiology,1994,25:87-94.
[10]Swenberg ML,Kelleher W J,Schwarting AE.Muscarine:isolation from cultures of Clitocybe rivulosa[J].Science,1967,155:1259.
[11]Garlaschelli L,Mellerio G,Vidari G,Vita-Finzi P.New fatty acid esters of drimane sesquiterpenes fiom Lactarius uvidus[J].Journal of Natural Products,1994,57:905-190.
[12]Park JK,Hasumi K,Endo A.Inhibition of acyI-CoA:cholesterol acyltransferase by helminthosporol and its related compounds[J].The Journal of Antibiotics,1993,46:1303-1305.
[13]Briquet M,Vilret D,Goblet P,Mesa M,Eloy MC.Plant cell membranes as biochemical targets of the phytotoxin helminthosporol[J].Journal of Bioenergetics and Biomembranes,1998,30:285-295.
[14]杨秀伟.天然药物化学发展的历史性变迁[J].北京大学学报(医学版),2004,36:9-11.
[15]孙汉董.活。性天然产物发现及作用机理研究的思路与方法[J].中国天然药物,2008,6:1.
[16]Newman D J,Cragg GM.Natural products as sources of new drugs over the last 25 years [J].Journal of Natural Products,2007,70:461-477.
[17]王普善.天然产物在新药发现中的地位与机会[J].精细与专用化学品,2006,14:1-5.
[18]Hawksworth DL,The fungal dimension of biodiversity:magnitude,significance,and conservation[J].Mycological Research,1991,95:641-655.
[19]卯晓岚.中国大型真菌[M].郑洲:河南科学技术出版社,2000.
[20]Lindequist U,Niedermeyer TH,D.JW.The pharmacological potential of mushroom[J].Evidence-Based Complementary and Alternative Medicine,2005,2:285-299.
[21]Berg A,Dorfelt H,Kiet TT,Schlegel B,Grafe U.Agrocybolacton,a new bioactive metabolite from Agrocybe sp.HKI 0259[J].The Journal of Antibiotics,2002,55:818-820.
[22]Anchel M,Hervey A,Robbins WJ.Production of Illudin M and of a Fourth Crystalline Compound by Clitocybe Illudens[J].Proceedings of the National Academy of Sciences of the United States of America,1952,38:927-928.
[23]McMorris TC,Anchel M.Fungal Metabolites.the Structures of the Novel Sesquiterpenoids llludin-S andM[J].Journal of the American Chemical Society,1965,87:1594-1600.
[24]Kawa.gishi H,Masui A,Tokuyama S,Nakamura T.Erinacines J and K from the mycelia of Hericium erinaceum[J].Tetrahedron,2006,62:8463-8466.
[25]Anchel M.Structure of diatretyne 2,an antibiotic polyacetylenic nitrile from Clitocybe diatreta[J].Science,1955,121:607-608.
[26]Tsuge N,Mori T,Hamano T,Tanaka H,Shin ya K,Seto H.Cinnatriacetins A and B,new antibacterial triacetylene derivatives from the fruiting bodies of Fistulina hepatica[J].The Journal of Antibiotics,1999,52:578-581.
[27]Kawagishi H,Ishiyama D,Mori H,Sakamoto H,Ishiguro Y,Furukawa S.Dictyophorines A and B,two stimulators of NGF-synthesis from the mushroom Dictyophora indusiata[J].Phytochemistry,1997,45:1203-1205.
[28]Hirokazu K,Atsushi S,Satoshi H,Hironobu M,Hideki S,Yukio I,et al.Erinacines E,F,and G,stimulators of nerve growth factor(NGF)-synthesis,from the mycelia of Hericium erinaceum.[J].Tetrahedron Letters,1996,37:7399-7402.
[29]Lee EW,Shizuki K,Hosokawa S,Suzuki M,Suganuma H,Inakuma T,et al.Two novel diterpenoids,erinacines H and I from the mycelia of Hericium erinaceum[J].Bioscience,biotechnology,and Biochemistry,2000,64:2402-2405.
[30]Kita T,Takaya Y,Oshima Y,Ohta T,Aizawa K,Hirano T,et al.Scabronines B,C,D,E and F,novel diterpenoids showing stimulating activity of nerve growth factor-synthesis,from the mushroom Sarcodon scabrosus[J].Tetrahedron Letters,1998,54:1877-1897.
[31]Cassinelli G,Lanzi C,Pensa T,Gambetta RA,Nasini G,Cuccuru G,et al.Clavilactones,a novel class of tyrosine kinase inhibitors of fungal origin[J].Biochemical Pharmacology,2000,59:1539-1547.
[32]Lee CH,Daanen JF,Jiang M,Yu H,Kohlhaas KL,Alexander K,et al.Synthesis and biological evaluation of clitocine analogues as adenosine kinase inhibitors[J].Bioorganic & Medicinal Chemistry Letters,2001,11:2419-2422.
[33]Withers SG,Umezawa K.Cyclophellitol:a naturally occurring mechanism-based inactivator of beta-glucosidases[J].Biochemical and Biophysical Research Communications,1991,177:532-537
[34]Park IH,Jeon SY,Lee H J,Kim Sl,Song KS.A beta-secretase(BACE1) inhibitor hispidin from the mycelial cultures of Phellinus linteus[J].Planta medica,2004,70:143-146.
[35]Umezawa H,Takeuchi T,Linuma H,Suzuki K,Ito M.A new microbial product,oudenone,inhibiting tyrosine hydroxylase[J].The Journal of Antibiotics,1970,23:514-518.
[36]Sharma VK,Choi J,Sharma N,Choi M,Seo SY.In vitro anti-tyrosinase activity of 5-(hydroxymethyl)-2-furfural isolated from Dictyophora indusiata[J].Phytother Res,2004,18:841-844.
[37]Liu DZ,Wang F,Liao TG,Tang JG,Steglich W,Zhu H J,et al.Vibralactone:a lipase inhibitor with an unusual fused b-lactone produced by cultures of the basidiomycete Boreostereum vibrans[J].Organic Letters,2006,8:5749-5752.
[38]Anke T,Hecht H J,Schramm G,Steglich W.Antibiotics from basidiomycetes.Ⅸ.Oudemansin,an antifungal antibiotic from Oudemansiella mucida(Schrader ex Fr.)Hoehnel(Agaricales)[J].The Journal of Antibiotics,1979,32:1112-1117.
[39]Anke T,Werle A,Bross M,Steglich W.Antibiotics from basidiomycetes.ⅩⅩⅩⅢ.Oudemansin Ⅹ,a new antifungal E-beta-methoxyacrylate from Oudemansiella radicata (Relhan ex Fr.) Sing[J].The Journal of antibiotics,1990,43:1010-1011.
[40]Anke T,Besl H,Mocek U,Steglich W.Antibiotics from basidiomycetes.ⅩⅧ.Strobilurin C and oudemansin B,two new antifungal metabolites from Xerula species(Agaricales)[J].The Journal of antibiotics,1983,36:661-666.
[42]Becker WF,von Jagow G,Anke T,Steglich W.Oudemansin,strobilurin A,strobilurin B and myxothiazol:new inhibitors of the bcl segment of the respiratory chain with an E-beta-methoxyacrylate system as common structural element[J].FEBS Letters 1981,132:329-333.
[43]Subik J,Behun M,Smigan P,Musilek V.Mode of action of mucidin,a new antifungal antibiotic produced by the basidiomycete Oudemansiella mucida[J].Biochimica et Biophysica Acta,1974,343:363-370.
[44]Anke T,Werle A,Bross M,Steglich W.Antibiotics from basidiomycetes.ⅩⅩⅩⅢ.Oudemansin Ⅹ,a new antifungal E-beta-methoxyacrylate from Oudemansiella radicata (Relhan ex Fr.) Sing[J].The Journal of Antibiotics,1990,43:1010-1011.
[45]Hwang El,Yun BS,Kim YK,Kwon BM,Kim HG,Lee HB,et al.Phellinsin A,a novel chitin synthases inhibitor produced by Phellinus sp.PL3[J].The Journal of Antibiotics,2000,53:903-911.
[46]Mo S,Wang S,Zhou G,Yang Y,Li Y,Chen X,et al.Phelligridins C-F:cytotoxic pyrano[4,3-c][2]benzopyran-l,6-dione and furo[3,2-c]pyran-4-one derivatives from the fungus Phellinus igniarius[J].Journal of Natural Products,2004,67:823-828.
[47]Kawagishi H,Ando M,Mizuno T.Hericenone A and B as cytotoxic principles from the mushroom Hericium erinaceum[J].Tetrahedron Letters,1990,31:373-376.
[48]Ren G,Zhao YP,Yang L,Fu CX.Anti-proliferative effect of clitocine from the mushroom Leucopaxillus giganteus on human cervical cancer HeLa cells by inducing apoptosis[J].Cancer Letters,2008,262:190-200.
[49]Oh GS,Hong KH,Oh H,Pae HO,Kim IK,Kim NY,et al. 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol isolated from the fruiting bodies of Isaria japonica YASUDA induces apoptosis of human leukemia cells(HL-60)[J].Biological &Pharmaceutical Bulletin,2001,24:785-789.
[50]Kim H J,Jang Sl,Kim YJ,Pae HO,Won HY,Hong KH.4-Acetyl-12,13-epoxyl-9-trichothecene-3,15-diol from Isaria japonica mediates apoptosis of rat bladder carcinoma NBT-Ⅱ cells by decreasing anti-apoptotic Bcl-2expression and increasing pro-apoptotic Bax expression[J].American Journal of Chinese Medicine,2004,32:377-387.
[51]Ye M,Liu Jk,Lu ZX,Zhao Y,Liu SF,Li LL,et al.Grifolin,a potential antitumor natural product from the mushroom Albatrellus confluens,inhibits tumor cell growth by inducing apoptosis in vitro[J].FEBS letters,2005,579:3437-3443
[52]Lin JT,Liu WH.O-orsellinaldehyde from the submerged culture of the edible mushroom Grifola frondosa exhibits selective cytotoxic effect against Hep3B cells through apoptosis [J].Journal of Agricultural and Food Chemistry,2006,54:7564-7569.
[53]Takei T,Yoshida M,Ohnishi-Kameyama M,Kobori M.Ergosterol peroxide,an apoptosis-induced component isolated from Sarcodon aspratus(Berk.) S.Ito[J].Bioscience,Biotechnology,and Biochemistry,2005,69:212-215.
[54]Hwang El,Kim JR,Jeong TS,Lee S,Rho MC,Kim SU.Phellinsin A from Phellinus sp.PL3 exhibits antioxidant activities[J].Planta Medica,2006,72:572-575.
[55]Wang Y,Wang S J,Mo SY,Li S,Yang YC,Shi JG.Phelligridimer A,a highly oxygenated and unsaturated 26-membered macrocyclic metabolite with antioxidant activity from the fungus Phellinus igniarius[J].Organic Letters,2005,7:4733-4736.
[56]Kim WG,Lee IK,Kim JP,Ryoo I J,Koshino H,Yoo ID.New indole derivatives with free radical scavenging activity from Agrocybe cylindracea[J].Journal of Natural Products,1997,60:721-723.
[57]Lauer U,Anke T,Hansske F.2-Methoxy-5-methyl-1,4-benzoquinone,a thromboxane A2receptor antagonist from Lentinus adhaerens[J].Journal of Antibiotics,1991,44-46.
[58]Saito T,Aoki F,Hirai H,Inagaki T,Matsunaga Y,Sakakibara T,et al.Erinacine E as a kappa opioid receptor agonist and its new analogs from a basidiomycete,Hericium ramosum[J].The Journal of Antibiotics,1998,51:983-990.
[59]Chibata I,Okumura K,Takeyama S,Kotera K.Lentinacin:a new hypocholesterolemic substance in Lentinus edodes[J].Experientia,1969,25:1237-1238.
[60]Kang HS,Choi JH,Cho WK,Park JC,Choi JS.A sphingolipid and tyrosinase inhibitors from the fruiting body of Phellinus linteus[J].Archives of Pharmacal Research,2004,27:742-750.
[61]Stadler M,Mayer A,Anke H,Sterner O.Fatty acids and other compounds with nematicidal activity from cultures of Basidiomycetes[J].Planta Medica,1994,60:128-132.
[62]Herrmann H.Identification of a metabolite of Clitocybe suaveolens as 4-methylnitrosaminobenzaldehyde[J].Hoppe-Seyler's Zeitschrift fur Physiologische Chemie,1961,326:13-16.
[63]Nair MS,Takeshita H,McMorris TC,Anchel M.Metabolites of Clitocybe illudens.Ⅳ.Illudalic acid,a sesquiterpenoid,and illudinine,a sesquiterpenoid alkaloid[J].The Journal of Organic Chemistry,1969,34:240-243.
[64]Sullivan G,Garrett RD,Lenehan RF.Occurrence of atromentin and thelephoric acid in cultures of Clitocybe subilludens[J].Journal of Pharmaceutical Sciences,1971,60:1727-1736.
[65]Teunissen P J,Swarts H J,Field JA.The de novo production of drosophilin A (tetrachloro-4-methoxyphenol) and drosophilin A methyl ether (tetrachloro-l,4-dimethoxybenzene) by ligninolytic basidiomycetes[J].Applied Microbiology and Biotechnology,1997,47:695-700.
[66]Shimazono H,Nord FF.Identification of methyl-p-coumarate as a metabolic product of Lentinus lepideus[J].Archives of Biochemistry and Biophysics,1958,78:263-264.
[67]Hirotani M,Sai K,Nagai R,Hirotani S,Takayanagi H,Yoshikawa T.Blazeispirane and protoblazeispirane derivatives from the cultured mycelia of the fungus Agaricus blazei.[J].Phytochemistry,2002,61:589-595.
[68]Hirotani M,Sai K,Hirotani S,Yoshikawa T.Blazeispirols B,C,E and F,des-A-ergostane-type compounds,from the cultured mycelia of the fungus Agaricus blazei[J].Phytochemistry,2002,59:571-577.
[69]Qian FG,Xu GY,Du S J,Li MH.Isolation and identification of two new pyrone compounds from the culture of Herictum erinaceus[J].Acta Pharmaceutica Sinica,1990,25:522-525.
[70]Kenmoku H,Shimai T,Toyomasu T,Kato N,Sassa T.Erinacine Q,a new erinacine from Hericium erinaceum,and its biosynthetic route to erinacine C in the basidiomycete[J].Bioscience,Biotechnology,and Biochemistry,2002,66:571-575.
[71]Bobek P,Ginter E,Jurcovicova M,Kuniak L.Cholesterol-lowering effect of the mushroom Pleurotus ostreatus in hereditary hypercholesterolemic rats[J].Annals of Nutrition &metabolism,1991,35:191-195.
[72]Jose N,Ajith TA,Janardhanan KK.Methanol extract of the oyster mushroom,Pleurotus florida,inhibits inflammation and platelet aggregation[J].Phytother Res,2004,18:43-46.
[73]Ajith TA,Janardhanan KK.Antioxidant and anti-inflammatory activities of methanol extract of Phellinus rimosus(Berk) Pilat[J].Indian Journal of Experimental Biology,2001,39:1166-1169.
[74]Ajith TA,Janardhanan KK.Antioxidant and antihepatotoxic activities of Phellinus rimosus (Berk) Pilat[J].Journal of Ethnopharmacology,2002,81:387-391.
[75]Ajith TA,Janardhanan KK.Cytotoxic and antitumor activities of a polypore macrofungus,Phellinus rimosus(Berk) Pilat[J].Journal of Ethnopharmacology,2003,84:157-162.
[76]Inagaki N,Shibata T,Itoh T,Suzuki T,Tanaka H,Nakamura T,et al.Inhibition of IgE-dependent mouse triphasic cutaneous reaction by a boiling water fraction separated from mycelium of Phellinus linteus[J].Evid Based Complement Alternat Med,2005,2:369-374.
[77]Song YS,Kim SH,Sa JH,Jin C,Lim C J,Park EH.Anti-angiogenic,antioxidant and xanthine oxidase inhibition activities of the mushroom Phellinus linteus[J].Journal of Ethnopharmacology,2003,88:113-116.
[78]Jang BS,Kim JC,Bae JS,Rhee MH,Jang KH,Song JC,et al.Extracts of Phellinus gilvus and Phellinus baumii inhibit pulmonary inflammation induced by lipopolysaccharide in rats [J]. Biotechnology Letters, 2004,26:31-33.
[79] Zhang Y, Mills GL, Nair MG. Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita [J]. Phytomedicine,2003,10:386-390.
[80] Sarkar S, Koga J, Whitley RJ, Chatterjee S. Antiviral effect of the extract of culture medium of Lentinus edodes mycelia on the replication of herpes simplex virus type 1 [J].Antiviral Research,1993,20:293-303.
[81 ] Abate D, Abraham WR. Antimicrobial metabolites from Lentinus crinitus [J]. The Journal of Antibiotics, 1994,47:1348-1350.
[82] Hirasawa M, Shouji N, Neta T, Fukushima K, Takada K. Three kinds of antibacterial substances from Lentinus edodes (Berk.) Sing. (Shiitake, an edible mushroom) [J].International Journal of Antimicrobial Agents , 1999,11:151-157.
[83] Hatvani N. Antibacterial effect of the culture fluid of Lentinus edodes mycelium grown in submerged liquid culture [J]. International Journal of Antimicrobial Agents,2001,17:71-74.
[84] Shimada Y, Morita T, Sugiyama K. Effects of Lentinus edodes on fatty acid and molecular species profiles of phosphatidylcholine in rats fed different levels of corn oil [J].Bioscience, Biotechnology, and Biochemistry, 2002,66:1759-1763.
[85] Luiz RC, Jordao BQ, da Eira AF, Ribeiro LR, Mantovani MS. Mechanism of anticlastogenicity of Agaricus blazei Murill mushroom organic extracts in wild type CHO (K(1)) and repair deficient (xrs5) cells by chromosome aberration and sister chromatid exchange assays [J]. Mutation Research , 2003,528:75-79.
[86] Kaneno R, Fontanari LM, Santos SA, Di Stasi LC, Rodrigues Filho E, Eira AF. Effects of extracts from Brazilian sun-mushroom (Agaricus blazei) on the NK activity and lymphoproliferative responsiveness of Ehrlich tumor-bearing mice [J]. Food Chem Toxicol,2004,42:909-916.
[87] Wang JC, Hu SH, Lee WL, Tsai LY. Antimutagenicity of extracts of Hericium erinaceus [J]. The Kaohsiung Journal of Medical Sciences, 2001,17:230-238.
[88] Choi WS, Kim CJ, Park BS, Lee SE, Takeoka GR, Kim DG, et al. Inhibitory effect on proliferation of vascular smooth muscle cells and protective effect on CCI(4)-induced hepatic damage of HEAl extract [J]. Journal of Ethnopharmacology ,2005,100:176-9.
[89] 刘吉开.高等真菌化学[M].北京:中国科学技术出版社,2004.
[90] Alberto A, Gabriele C, Gianluca N, Roberta S. Isolation and structure elucidation of new sesquiterpenes of protoilludane origin from the fungus Clavicorona divaricata [J].Tetrahedron, 2003, 59:5033-5039.
[91] Arnone A, De Gregorio C, Meille SV, Nasini G, Sidoti G. Tsugicoline E, a New Polyoxygenated Protoilludane Sesquiterpene from the Fungus Laurilia tsugicola [J].Journal of Natural Products, 1999, 62:51-54.
[92] Krawczyk E, Luczak M, Kniotek M, Majewska A, Kawecki D, Nowaczyk M. Immunomodulatory activity and influence on mitotic divisions of N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols in vitro [J]. Planta Medica,2005,71:819-824.
[93]McMorris TC,Lira R,Gantzel PK,Kelner M J,Dawe R.Sesquiterpenes from the basidiomycete Omphalotus illudens[J].Journal of Natural Products,2000,63:1557-9.
[94]Forster PG,Ghisalberti EL,Jefferies PR.The chemistry of Eremophila spp.XXVIII.A new class of monocyclic diterpenes from Eremophila foliosissima Kraenzlin[J].Tetrahedron,1987,43:2999-3007.
[95]Ciuffreda P,Casati S,Manzocchi A.Spectral assignments and reference data complete ~1H and ~(13)C NMR spectral assignment of α-and β-adenosine,2'-deoxyadenosine and their acetate derivatives[J].Magnetic Resonance in Chemistry,2007,45:781-784.
[96]Yuan JP,Zhao SY,Wang JH,Kuang HC,Liu X.Distribution of Nucleosides and Nucleobases in Edible Fungi[J].Journal of Agricultural and Food Chemistry,2008,56:809-814.
[97]李敬轩,张敬贤.从猴头菌得到的2种新的生理活性物质[J].吉林农业大学学报1998.20:171.
[98]Williams EA,Donahue PE,Cargioli JD.Nuclear magnetic resonance determination of the effect of end-capping ratio on the structure of bisphenol A polycarbonate-poly(dimethylsiloxane) block copolymers[J].Macromolecules,1981,141016-1018.
[99]Gebhardt P,Dornberger K,Gollmick F,Grafe U,Hartl A,Gorls H,et al.Quercinol,an anti-inflammatory chromene from the wood-rotting fungus Daedalea quercina(Oak Mazegill)[J].Bioorganic & Medicinal Chemistry Letters,2007,17:2558-2560.
[100]Abraham WR,Abate D.Chromanones from Lentinus crinitus[J].Z Naturforsch,C:Biosciences,1995,50:748-751.
[101]Lauer U,Anke T,Hansske F.Antibiotics from basidiomyceles.ⅩⅩⅩⅧ.2-Methoxy-5-methyl-1,4-benzoquinone,a thromboxane A2 receptor antagonist from Lentinus adhaerens[J].The Journal of Antibiotics,1991,44:59-65.
[102]Dmitrenok AS,Anjaneyulu V,Rao PVS,Radhika P,Dmitrenok PS,Boguslavsky VM,et al.Glycosphingolipid with a branched sphingosine base from soft corals from the Andaman Islands[J].Russian Chemical Bulletin(Translation of Izvestiya Akademii Nauk,Seriya Khimicheskaya),2001,20:1474-1477.
[103]Takei T,Yoshida M,Ohnishi-Kameyama M,Kobori M.Ergosterol peroxide,an apoptosis-induced component isolated from Sarcodon aspratus(Berk.) S.Ito[J].Bioscience,Biotechnology,and Biochemistry,2005,69:212-215.
[104]Ngai PH,Zhao Z,Ng TB.Agrocybin,an antifungal peptide from the edible mushroom Agrocybe cylindracea[J].Peptides,2005,26:191-196.
[105]Ayer WA,Craw PA,Stout T J,Clardy J.Novel sesquiterpenoids from the fairy ring fungus,Marasmius oreades[J].Canadian Journal of Chemistry,1989,67:773-778.
[106]Arnone A,Cardillo R,Nasini G,Vajna de Pava O.Secondary mold metabolites:part 46.Hericenes A-C and erinapyrone C,new metabolites produced by the fungus Hericium erinaceus[J].Journal of natural products,1994,57:602-606.
[107]Kenmoku H,Sassa T,Kato N.Isolation of erinacine P,a new parental metabolite of cyathane-xylosides,from Hericium erinaceum and its biomimetic conversion into erinacines A and B[J].Tetrahedron letters,2000,41:4389-4393.
[108] Castells J, Jones ERH, Meakins GD, William RWJ. Steroids of natural configuration I.Stereochemistry of lumisterol and 9a-lumisterol (pyrocalciferol) [J]. Journal of the Chemical Society, 1959:1159-1168.
[109] Kupchan SM, Aynehchi Y, Cassady JM, Schnoes HK, Burlingame AL. Tumor inhibitors XL. The isolation and structural elucidation of elephantin and elephantopin, two novel sesquiterpenoid tumor inhibitors from Elephantopus elatus [J]. The Journal of organic Chemistry ,1969,34:3867-3875.
[110] Kupchan SM, Kelsey JE, Maruyama M, Cassady JM. Eupachlorin acetate, a novel chloro-sesquiterpenoid lactone tumor inhibitor from Eupatorium rotundifolium [J].Tetrahedron Letters ,1968,31:3517-3520.
[111] Fischel JL, Lemee R, Formento P, Caldani C, Moll JL, Pesando D, et al. Cell growth inhibitory effects of caulerpenyne, a sesquiterpenoid from the marine algae Caulerpa taxifolia [J]. Anticancer Research ,1995,15:2155-160.
[112] Narisawa T, Fukaura Y, Kotanagi H, Asakawa Y. Inhibitory effect of cryptoporic acid E, a product from fungus Cryptoporus volvatus, on colon carcinogenesis induced with N-methyl-N-nitrosourea in rats and with 1,2-dimethylhydrazine in mice [J]. J Cancer Res, 1992,83:830-834.
[113] Casapullo A, Minale L, Zollo F. Paniceins and related sesquiterpenoids from the Mediterranean sponge Reniera fulva [J]. Journal of Natural Products, 1993,56:527-533.
[114] Woynarowski JM, Napier C, Koester SK, Chen SF, Troyer D, Chapman W, et al. Effects on DNA integrity and apoptosis induction by a novel antitumor sesquiterpene drug,6-hydroxymethylacylfulvene (HMAF, MGI 114) [J]. Biochemical Pharmacology,1997,54:1181-1193.
[115] Cervia D, Martini D, Garcia-Gil M, Di Giuseppe G, Guella G, Dini F, et al. Cytotoxic effects and apoptotic signalling mechanisms of the sesquiterpenoid euplotin C, a secondary metabolite of the marine ciliate Euplotes crassus, in tumour cells [J]. Apoptosis,2006,11:829-843.
[116] Cervia D, Garcia GM, Simonetti E, Di Giuseppe G, Guella G, Bagnoli P. Molecular mechanisms of euplotin C-induced apoptosis: involvement of mitochondrial dysfunction,oxidative stress and proteases [J]. Apoptosis,2007,12:1349-1363.
[117] El-Gamal AA, Chiu EP, Li CH, Cheng SY, Dai CF, Duh CY. Sesquiterpenoids and norsesquiterpenoids from the Formosan soft coral Lemnalia laevis [J]. Journal of Natural Products, 2005,68:1749-1753.
[118] Triana J, Lopez M, Rico M, Gonzalez-Platas J, Quintana J, Estevez F. Sesquiterpenoid derivatives from Gonospermum elegans and their cytotoxic activity for HL-60 human promyelocytic cells [J]. Journal of Natural Products ,2003,66:943-948.
[119] Kobayashi J, Murayama T, Ohizumi Y, Ohta T, Nozoe S, Sasaki T. Metachromin C, a new cytotoxic sesquiterpenoid from the Okinawan marine sponge Hippospongia metachromia [J]. Journal of Natural Products,1989,52:1173-1177.
[120] McConnell OJ, Longley R, Gunasekera M. Isometachromin, a new cytotoxic sesquiterpenoid from a deep water sponge of the family Spongiidae [J]. Experientia,1992,48:891-892.
[121] Stark A, Anke T, Mocek U, Steglich W, Kirfel A, Will G. Lentinellic acid, a biologically active protoilludane derivative from Lentinellus species (Basidiomycetes) [J]. Zeitschrift fur Naturforschung ,1988,43:177-183.
[122] Cheah YH, Azimahtol HL, Abdullah NR. Xanthorrhizol exhibits antiproliferative activity on MCF-7 breast cancer cells via apoptosis induction [J]. Anticancer Research,2006,26:4527-4534.
[123] Posadas I, Terencio MC, Giannini C, D'Auria MV, Paya M. Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase [J]. European Journal of Pharmacology, 2001,415:285-292.
[124] Carter CJ, Cannon M. Inhibition of eukaryotic ribosomal function by the sesquiterpenoid antibiotic fusarenon-X [J]. European Journal of Biochemistry / FEBS ,1978,84:103-111.
[125] Mierau V, Anke T, Sterner O. Dacrymenone and VM 3298-2-new antibiotics with antibacterial and antifungal activity [J]. Zeitschrift fur Naturforschung, 2003,58:541-546.
[126] Suh YG, Kim SN, Shin DY, Hyun SS, Lee DS, Min KH, et al. The structure-activity relationships of mansonone F, a potent anti-MRSA sesquiterpenoid quinone: SAR studies on the C6 and C9 analogs [J]. Bioorganic & Medicinal Chemistry Letters,2006,16:142-145.
[127] McCallion RF, Cole AL, Walker JR, Blunt JW, Munro MH. Antibiotic substances from New Zealand plants. II. Polygodial, an anti-Candida agent from Pseudowintera colorata [J].Planta Medica ,1982,44:134-138.
[128] Bruno M, Rosselli S, Maggio A, Raccuglia RA, Napolitano F, Senatore F. Antibacterial evaluation of cnicin and some natural and semisynthetic analogues [J]. Planta Medica,2003,69:277-281.
[129] Olila D, Opuda-Asibo J, Olwa O. Bioassay-guided studies on the cytotoxic and in vitro trypanocidal activities of a sesquiterpene (Muzigadial) derived from a Ugandan medicinal plant (Warburgia ugandensis) [J]. African Health Sciences, 2001,1:12-15.
[130] Momose I, Sekizawa R, Hosokawa N, linuma H, Matsui S, Nakamura H, et al. Melleolides K, L and M, new melleolides from Armillariella mellea [J]. The Journal of Antibiotics,2000,53:137-143.
[131] Abbanat DA, Singh MP, Greenstein M. Hongoquercins, new antibacterial agents from the fungus LL-23 g227: fermentation and biological activity [J]. The Journal of Antibiotics 1998,51:708-714.
[132] Roll DM, Manning JK, Carter GT. Hongoquercins A and B, new sesquiterpenoid antibiotics:isolation, structure elucidation, and antibacterial activity [J]. The Journal of Antibiotics 1998,51:635-639.
[133] Simon B, Anke T, Anders U, Neuhaus M, Hansske F. Collybial, a new antibiotic sesquiterpenoid from Collybia confluens (Basidiomycetes) [J]. Zeitschrift fur Naturforschung ,1995,50:173-80.
[134] Erkel G, Anke T, Velten R, Gimenez A, Steglich W. Hyphodontal, a new antifungal inhibitor of reverse transcriptases from Hyphodontia sp. (Corticiaceae, Basidiomycetes) [J].Zeitschrift fur Naturforschung, 1994,49:561-570.
[135] Kupka J, Anke T, Mizumoto K, Giannetti BM, Steglich W. Antibiotics from basidiomycetes. XVII. The effect of marasmic acid on nucleic acid metabolism [J]. The Journal of Antibiotics ,1983,36:155-160.
[136] Garzon SP, Rodriguez AD, Sanchez JA, Ortega-Barria E. Sesquiterpenoid metabolites with antiplasmodial activity from a Caribbean gorgonian coral, Eunicea sp [J]. Journal of Natural Products, 2005,68:1354-1359.
[137] Tchuendem MH, Mbah JA, Tsopmo A, Ayafor JF, Sterner O, Okunjic CC. Anti-plasmodial sesquiterpenoids from the African Reneilmia cincinnata [J]. Phytochemistry,1999,52:1095-1099.
[138] Fuchino H, Koide T, Takahashi M, Sekita S, Satake M. New sesquiterpene lactones from Elephantopus mollis and their leishmanicidal activities [J]. Planta Medica ,2001,67:647-653.
[139] Jordao CO, Vichnewski W, de Souza GE, Albuquerque S, Lopes JL. Trypanocidal activity of chemical constituents from Lychnophora salicifolia Mart [J]. Phytother Res ,2004,18:332-334.
[140] Krawczyk E, Luczak M, Kobus M, Banka D, Daniewski W. Antiviral activity of N-benzoylphenylisoserinates of Lactarius sesquiterpenoid alcohols in vitro [J]. Planta Medica, 2003,69:552-554.
[141] Hoang VD, Tan GT, Zhang HJ, Tamez PA, Hung NV, Cuong NM, et al. Natural anti-HIV agents-part I: (+)-demethoxyepiexcelsin and verticillatol from Litsea verticillata [J].Phytochemistry , 2002,59:325-329.
[142] Singh SB, Felock P, Hazuda DJ. Chemical and enzymatic modifications of integric acid and HIV-1 integrase inhibitory activity [J]. Bioorganic & Medicinal Chemistry Letters,2000,10:235-238.
[143] Lim CS, Jin DQ, Mok H, Oh SJ, Lee JU, Hwang JK, et al. Antioxidant and antiinflammatory activities of xanthorrhizol in hippocampal neurons and primary cultured microglia [J]. Journal of Neuroscience Research, 2005,82:831-838.
[144] Hernandez V, Manez S, Recio MC, Giner RM, Rios JL. Anti-inflammatory profile of dehydrocostic acid, a novel sesquiterpene acid with a pharmacophoric conjugated diene [J]. Eur J Pharm Sci, 2005,26:162-169.
[145] Lucas R, Giannini C, D'Auria M V, Paya M. Modulatory effect of bolinaquinone, a marine sesquiterpenoid, on acute and chronic inflammatory processes [J]. The Journal of Pharmacology and Experimental Therapeutics, 2003,304:1172-1180.
[146] Hernandez V, del Carmen Recio M, Manez S, Prieto JM, Giner RM, Rios JL. A mechanistic approach to the in vivo anti-inflammatory activity of sesquiterpenoid compounds isolated from Inula viscose [J]. Planta Medica, 2001,67:726-731.
[147] Segura L, Freixa B, Ringbom T, Vila R, Perera P, Adzet T, et al. Anti-inflammatory activity of dichloromethane extract of Heterotheca inuloides in vivo and in vitro [J]. Planta Medica,2000,66:553-555.
[148] Tsai YC, Hsu HC, Yang WC, Tsai WJ, Chen CC, Watanabe T. Alpha-bulnesene, a PAF inhibitor isolated from the essential oil of Pogostemon cablin [J]. Fitoterapia, 2007,78:7-11.
[149] Tsuneki H, Ma EL, Kobayashi S, Sekizaki N, Maekawa K, Sasaoka T, et al. Antiangiogenic activity of beta-eudesmol in vitro and in vivo [J]. European Journal of Pharmacology, 2005,512:105-115.
[150] Nambiar MP, Murugesan R, Wu HC. Inhibition of the cytotoxicity of protein toxins by a novel plant metabolite, mansonone-D [J]. Journal of Cellular Physiology, 1998,176:40-49.
[151] Yamahara J, Li YH, Tamai Y. Anti-ulcer effect in rats of bitter cardamon constituents.Chemical & Pharmaceutical Bulletin,1990,38:3053-3054.
[152] Matsuda H, Yamahara J, Kobayashi G, Fujimura H, Kurahashi K, Fujiwara M. Effect of alismol on adrenergic mechanism in isolated rabbit ear artery [J]. Japanese Journal of Pharmacology ,1988,46:331-335.
[153] Neufeld E, Sklarz B, Goldberg S, Gilad S, Goldfarb H, Laurian L, et al. Observations on the chemical and physiological properties of urodiolenone, an urinary compound found in hypertension [J]. Nephron, 1985,39:146-148.
[154] Rosenthal T, Grossman E, Goldberg S, Peleg E, Chayen R. Urinary output of urodiolenone in essential hypertension [J]. Am J Hypertens, 1989,2:449-452.