摘要
本论文首次报道了利用蛹虫草菌作为生物转化体系对天然产物进行结构修饰。通过系统的研究,确定了蛹虫草菌液体培养条件:培养基的组成为:培养基的成分为蔗糖(6.0%),蛋白胨(0.4%),硫酸镁(0.05%),氯化钙(0.01%),磷酸二氢钾(0.1%);培养条件为接种量(10%)、发酵温度(24℃)、发酵起始PH(6.0)、转速(150rmp)和光照(弱光)。并对培养液的化学成分进行了研究,分离出32个化合物,鉴定了29个化合物分别为:β-谷甾醇(C-1);2-乙基酮-3-羟基-4H吡喃酮(C-2);7,8-二甲基-异咯嗪(C-3);6-异丁基-吡咯并[1,2a]六氢吡嗪-1,4-二酮(C-4);6-苄基-吡咯并[1,2a]六氢吡嗪-1,4-二酮(C-5);6-异丙基-吡咯并[1,2a]六氢吡嗪-1,4-二酮(C-6);3,7,8-三甲基-异咯嗪(C-7);1-甲酰基-苯并咪唑(C-8);3-乙基-4-羟基-6-甲基-2H-吡喃-2-酮(C-9);胡萝卜苷(C-10);6-甲基-吡咯并[1,2a]六氢吡嗪-1,4-二酮(C-11);1-甲基-6-异丁基-2,5-哌嗪二酮(C-12);1-异丙基-6-异丁基-2,5-哌嗪二酮(C-13);虫草酸(C-14);琥珀酸(C-15);尿嘧啶(C-16);2-甲基-3-羟基吡啶(C-17);胸腺嘧啶(C-18);1-羟甲基-6-异丁基-2,5-哌嗪二酮(C-19);虫草素(C-20);腺苷(C-21);3,6-二(对羟基苄基)-2,5-哌嗪二酮(C-22);2-吲哚乙基丁二酰胺(C-23);1-(5-羟甲基)-呋喃-3-羧基-β-咔啉(C-24);3-乙酰胺基-6-异丁基-2,5-哌嗪二酮(C-25);3,6-二(3-甲基吲哚)-2,5-哌嗪二酮(C-26);鸟苷(C-27);5-异丁基-3,6-氧代-2-哌嗪丙酸(C-28)和麦角甾-7,22-二烯-3β,5,6-三醇(C-29)。其中3-乙酰胺基-6-异丁基-2,5-哌嗪二酮(C-25)为未见文献报道的新化合物。化合物C-8、C-22和C-23为新天然产物。
利用建立起来的蛹虫草菌及其它多种生物转化体系对去氢木香内酯,木香烯内酯和莪二酮进行了生物转化研究。
从38种微生物中筛选出,蛹虫草菌和多型孢毛霉对去氢木香内酯进行了生物转化研究。共分离得到9个化合物,分别为:去氢木香内酯(1);11α,13-二氢去氢木香内酯(2);
It was firstly reported that Cordyceps militaris could be used to transform the nature products. The fermentation medium of C. militaris as a biotransformation system was optimized by systemic analysis of the flask fermentation included sugar (6%), yeast extract (0.4%), MgSO_4 (0.05%); CaCl_2(0.01%) and KH-2PO_4(0.1%). The optimum fermentation conditions were 10% of inoculated volume in fermentation condition of fermenting temperature 24 °C, the initial PH value (6.0) and small light needed. At the same time, we studied the chemical constituents in the liquid culture of Cordyceps militaris by various chromatographic methods. 32 compounds were obtained from the liquid culture and the structures of 29 compounds were identified as P-sitosterol (C-l); 2-ethyl-3-hydroxy, 4H-pyran-4-one(C-2); 7, 8-dimethyl-isoalloxazine (C-3); 6-isobutyl-pyrorolo [1,2a] hexahydropyrazine-1, 4-dione (C-4); 6-benzyl-pyrrolo [1,2a] hexahydropyrazine-1, 4- dione (C-5); 6-isopropyl-pyrrolo [1,2a] hexahydropyrazine-1, 4-dione (C-6); 3, 7, 8-trimethyl -isoalloxazine (C-7); 1-formyl-benzpyrazole (C-8); 2H-pyran-2-one, 3-ethyl-4-hydroxy-6-methyl (C-9) ; daucosterol (C-10) ; 6-methyl-pyrorolo [1, 2a] hexahydropyrazine-1, 4-dione (C-11); l-methyl-6-isobutyl-2, 5-piperazine-dione (C-12); l-isopropyl-6-isobutyl-2, 5-piperazine-dione (C-13); D-mannitol (C-14); succinic acid (C-15); uracil (C-16); 2-methyl- 3-hydroxy- pyrolidine (C-17); thymine (C-18); l-hydroxymethyl-6-isobutyl-2, 5-piperazine-dione (C-19); cordycepin (C-20); adenosine (C-21); 3, 6-di-(p-hydroxybenzyl)- 2, 5-piperazine-dione (C-22); succinamide, N, N-bis- [2-(3-indol) -ethyl] (C-23); flazin (C-24); 3- acetamino- 6-isobutyl -2, 5-piperazine-dione (C-25); 3, 6- bis-(3-methyl-indole)-2, 5- piperazine -dione (C-26); guanosin (C-27); 5-isobutyl -3, 6-dioxo-2- piperazinepanoic acid (C-28); ergosta-7, 22-diene-3β, 5, 6-triol (C-29). Among them, 3-acetamino - 6-isobutyl-2, 5-piperazine-dione (C-25) is a new compound. The compounds C-8,
引文
[1] Loughlin W A. Biotransformations in organic synthesis. Bioresource Technol. 2000, 74:49-62.
[2] Rozzell J D. Commerical scale biocatalysis: myths and realities. Bioorg. Med .Chem. 1999, 7:2253-2261.
[3] Giri A, Dhingra V, Giri C C. Biotransformation using plant cells, organ cultures and enzyme systems: current trends and future prospects. Biotechnol. Adv. 2001, 19:175-199.
[4] Sebek O K. Notes on the historical development of microbial transformation. In: Rosazza JP, ed. Microbial transformation bioactive compounds (Vol. I). Florida: CRC press. 1982, 1-8.
[5] Riva S. Biocatalysis modification of natural products. Curr Opin. Chem. Bio. 2001, 5:106-111.
[6] Clark A M, Hufford C D. Use of microoganisms for the study of drug metablism: an update. Med Res Rev. 1991, 11:473-501.
[7] Abourashed E A, Clark A M, Hufford C D. Microbial modify mammalian metabolism of xenobiotics: an updated review. Curr. Med. Chem. 1999, 6:359-374.
[8] Azerad R. Microbial models for drug metabolism. In: Scheper T,ed. Advances in biochemical engineering/biotechnology. Vol.63: Biotransformations. Berlin: Springer verlag. 1999, 169-218.
[9] Hirata T, Aoki T, Hirano Y, Suga T. The biotransformation of foreign substrates by tissue cultures. I. The hydroxylation of linalool and its related compounds with the suspension cells of Nicotiana tabacum. Bull. Chem. Soc. Jpn. 1981, 54: 3527-3529.
[10] Suga T, Aoki T, Hirano Y, Lee Y S. Biotransformation of Foreign substrates with callus tissue. Transformation of terpinols with Tobacco suspension cells. Chem. Lett. 1980, 229-231.
[11] Lee Y S. The enantiselective biotransformation of α-terpinol and its acetate with the cultured cells of nicotiana tabacum. J. Sci. Ser. A. 1983, 47:21-25.
[12] Hirata T, Lee Y S, Suga T. The stereopecific hydroxylation of endocyclic ehtylenic linkage in the biotransformation of α-terpinyl acetate with cultured suspension cells of nicotiana tabacum. Chem. Lett. 1982, 671-673.
[13] Lee Y S, Suga T, Hirata T J. 1-acetoxy-p-menth-4(8)-ene with a suspension of cultured cells of Nicotiana tabacum. Chem. Soc. Perkin Trans. Ⅰ. 1983, 2475-2478.
[14] 宁黎丽.雷公藤甲素和雷公藤内酯酮的生物转化研究.沈阳药科大学博士学位论文.
[15] Ye M, Ning L L, Zhan J X. Biotransformation of cinobufagin by cell suspension cultures of Catharathus roseus and Platycidon grandiflorum. Journal of Molecular Catalysis B: Enzymatic. 2003, 22:89-95.
[16] Li lixing桔梗等植物体系对于酯蟾毒配基等四种天然产物的生物转化研究.北京大学硕士论文.
[17] 赵军.蟾毒灵生物转化及酯蟾毒配基植物细胞转化动态研究.北京大学博士后研究工作报告.
[18] Cheng K D, Chen W M, Zhu W H. Int. Appl. WO 9406,740 (CI.CO7035137), 31 Mar 1994, JP Appl. 92/249,047, 18 sep 1992.
[19] Dai J G. Ye M. Biotransformation of 2α, 5α, 10β, 14β-tetraactoxy-4(20), 11-taxadiene by gingko cell suspension cultures. Tetrahedron. 2002, 58:5659-5661.
[20] Dai J G, Guo H Z. Biotransformation of 2α, 5α, 10β, 14β-tetraactoxy-4(20), 11-taxa-diene by Catharanthus roseus cell suspension culture. Tetrahedron lett. 2001, 42:4677-4679.
[21] Suga T, Hirata T, Lee Y S, Suga T. The enantiselective biotransformation of α-terpinol and its acetate with the cultured cells of nicoticma tabacum. Chem. Lett. 1982, 1595-1597.
[22] Hirata T, Izumi S, Ekida T, Suga T. Hydroxylation of acetoxy-p-menthenens in the cultured cells of nicotiana tabacum, expoxidate of the carbon-carbon double bond. Bull. Chem. Soc. Jpn. 1987, 60: 289-292.
[23] Furuya T, Kawaguchi K, Hirotani M. Biotransformation of 10-hydroxygeraniol and related compounds by cell suspension culture of Catharathus roseus: the formation of related products. Phytochemistry 1988, 27:2129-2132.
[24] Banthorpe D V, Osborne M J. Terpene epoxidases and epoxide hydratases from cultures of Jasminum officinale. Phytochemistry 1984, 23: 905-908.
[25] Hamada H. Bull. Chem. Soc. Jpn. 1988, 60: 289-292.
[26] Suga T, Izumi S, Hirata T, Hamada H. Stereoselectivity in oxidation and reductive with the cultured cells of nicotiana tabacum. Chem. Lett. 1987, 425-427.
[27] Suga T, Hirata T. Nippon Kagaku Kaishi Peroxidase catalysed incorporation into polymers as a major pathway of hordenine metabolism in barley cell suspension cultures. Phytochemistry 1983, 21:1385-1387.
[28] Takashi H, Massaki O, Masanokr K. Biotransformation of the germacrane type sesquiter-pene curdione by suspension cultured cells of Lonicera japonica. Phytochemistry 1997, 44:627-632.
[29] Hiroshi S. Biotransformation of α-ionone and β-ionone by cultured cells of Caragana chamlagu. Journal of molecular Catalysis B: Enzymatic 2004, 27:177-178.
[30] Hiroshi S. Biotransformation of thujopsene by Caragana chamlagu. J. Nat. Prod. 1997, 64:630-631.
[31] Bolwell G P, Bozak K, Zimmerlin A. Plant cytochrome P450. Phytochemistry 1994, 37:14915-14918.
[32] Hirata T, Hamada H, Aoki T, Suga T. Stereoselectivity of the reduction of carvone and dihydrocarvone by suspension cells of Nicotiana tabacum. Phytochemistry 1982, 21: 2212-2214.
[33] Aviv D, Krochmal E, Dantes A, Galun E. Biotransformation of monoterpenes by menthe cell lines: conversion of menthone to neomenthol. Planta Med. 1981, 42: 236-237.
[34] Suga T, Hamada H, Hirata T, Izumi S. Stereoselectivity in oxidation and reductive with the cultured cells of nicotiana tabacum. Chem. Lett. 1987, 903-906.
[35] 宁黎丽.雷公藤甲素和雷公藤内酯酮的生物转化研究.沈阳药科大学博士学位论文.
[36] suga T, Hirata T. Biotransformation of 3-oxo-p-menthane derivations by cultured cells of nicotiana tabcum. Phytochemistry 1988, 27:1041-1043.
[37] Suga T, Hamada H, Hirata T. Enatiosclectivity in the biotransformation of biocyclo [3.1.1] heptanes with the cultured cells of nicotiana tabacum. Chem. Lett. 1987, 471-474.
[38] Nakamura K, Miyoshi H, Sugiyama T, Hamada H. Diastereo- and enantio-selective reduction of ethyl 2-methyl-3-oxobutanoate by plant cell cultures. Phytochemistry 1995, 40:1419-1422.
[39] Chadha A, Manohar M. Soundararajan T, Lokeswari T S. Asymmetric reduction of 2-oxo-4-phenylbutanoic acid ethyl ester by Daucus carota cell cultures. Tetrahedron: Asymmetry 1996, 7:1571-1573.
[40] Balsevich J. Biotransformation of 10-hydroxygeraniol and related compounds by cell suspension culture of Catharathus roseus: the formation of related products. Planta Med. 1985, 128-129.
[41] Zeng Y C, Elbein A D. Purification to homogeneity and proprties of plant glucosidase. Arch. Biochem. Biophys. 1998, 35(5):26-29.
[42] Teus J C, LuudendukA N, Verpoorte R. Strictosidine glucosidase from suspension cultured cells of Tabernaemontana divaricata. Phytochemistry 1996, 41:1415-1417.
[43] Yokoyama M. In plant cell culture- secondary metabolism: Toward industrial application; Frank Dicosmo and Masanaru misawa, Eds. Industrial application of biotransformation using plant cell cultures; CRC press: Florida 1996; pp79-121.
[44] Archama G, Vikas D, Gift C C. Biotransformation using plant cells, organ cultures and enzyme systems: current trends and future prospects. Biotechnol. adv. 2001, 19:175-178.
[45] Pedras M S C, Zaharia I L, Gai Y. In planta sesquential hydroxylation and glucosylation of a fungal phytotoxin: avoiding cell death and overcoming the fugal invader. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:747-749.
[46] Furuya T, Ushiyama M, Ashida Y, Yoshikawa T. Biotransformation of 2-phenylpropionic acid in root culture of Panax ginseng. Phytochemistry 1989, 28:483-485.
[47] Furuya T, Ushiyama M, Ashida Y, Yoshikawa T. Glycosylation of 2-phenyl -propionic acid and its ethyl ester in suspension cultures ofNicotiana tabacum, Dioscoreophyllum cumminsii and Aconitum japonicum. Phytochemistry 1987, 26:2983-2988.
[48] Furuya T, Ushiyama M, Ashida Y, Yoshikawa T, Orihara Y. Biotransformation of phenylacetic acid and 2-phenyl- propionic acid in suspension culture of offea arabica. Phytochemistry 1988, 27: 803-805.
[49] Ushiyama M, Asada T, Yoshikawa T, Furuya T. Biotransformation of aromatic carboxylic acids by root culture of Panax ginseng. Phytochemistry 1989, 28:1859-1862.
[50] Moyer B G, Gustine D L. Esterification of 3-nitropropanoic acid to glucose by suspension cultures of Coronilla varia. Phytochemistry 1987, 26:139-142.
[51] Tabata M, Unetani Y, Oya M, Tanaka S. Glucosylafion of phenolic compounds by plant cell cultures. Phytochemistry 1988, 27:809-812.
[52] Tabata M, Umetani Y, Shima K, Tanaka S. Biotransformation ofphenylcarboxylic acides by plant cell. Plant Cell Tissue Org. Cult. 1984, 3:3-6.
[53] Mizukami H, Terao T, Amano A, Ohashi H. Glucosylayion of cycodextrin complexed podophyllotoxin by cell cultures of linum flavum. Plant Cell Physiol. 1986, 27: 645-646.
[54] Mizukami H. Syokubutsu Soshiki Baiyo 1986, 3: 35.
[55] Suga T, Hirata T, Izumi S. Enantioselectivity in the hydrolysis of bicyclic monoterpene acetates with the cultured cells of Nicotiana tabacum. Phytochemistry. 1986, 25:2791-2793.
[56] Pawlowicz P, Piatkowski, Siewinski A. Enantiospecific hydrolysis of acetates of racemic monoterpenic alcohols by Spirodela oligorrhiza. Phytochemistry 1988, 27:2089-2091.
[57] Suga T, Hirata T, Futatsugi M. The biotransformation of carvoxime and dihydrocarvoxime with cell suspension cultures of Nicotiana tabacum. Phytochemistry 1984, 23: 1327-1329.
[58] Tan W H J, Kurz W G W, Constabel F, Chatson K B. 8-hydroxydihydro chelery- thrine and arnottianamide from roots of Toddalia asiatica. Phytochemistry 1982, 21:253-256.
[59] Williams P D, Mavituna F. Immobilized plant cells. In: Fowler MW, Warren GS, Moo Yong M, editors. Plant biotechnology. Oxford: Pergamon 1992.63-78.
[60] Brodelius P, Deus B, Mosbach K, Zenk M H. Immobilized plant cells for the production and transportation of natural products. FEB S Lett. 1979, 103:93-95.
[61] Brodelius P, Nilsson K. Entrapment of plant cells in different matrices: A comparative study. FEBS Lett. 1980, 122:312-315.
[62] Londsey K, Yoeman M M, Black G M, Mavituna F. A novel method for the immobilisation and culture of plant cells. FEBS Lett. 1983, 155:143-146.
[63] Lindsey K, Morris P, Scragg A H, Stafford A, Fowler M W. Secondary Metabolism in Plant Cell Cultures, Cambridge University Press, London. 1986, p. 143.
[64] Kutney J P. Plant cell culture and synthesis chemistry-routes to clinically important compounds "phytochenical and potential of tropical plants." Plenum Press. New York. 1993, 235-265.
[65] Aleu J, Collado I G. Biotransformation by Botrytis species. J. Mol. Catal. B: Enzym. 2001, 13:77-93.
[66] Grogan G J, Holland H L. The biocatalytic reaction of Beaureria spp. J. Mol. Catal. B: enzym. 2000, 9:1-32.
[67] Steinreiber A, Faber K. Microbial epoxide hydrolases for preparative biotransformations. Curr. Opin. Biotechnol. 2001, 12:552-558.
[68] Demain A L. The economic power of the microbe. Biotechnol. Adv. 2000, 18:499-514.
[69] Davis B G. Biocatalysis and enzymes in organic synthesis. Nat. Prod. Rep. 2001, 18:618-640.
[70] 郭勇主编.酶工程.北京:中国轻工业出版社.1994,5-7.
[71] Goeta M. Partie Ⅲ: Oxo-11-et, Oxo-12-bufalines, steroids defensifs deslampyres photinusignites marginellus. Helv. Chi. Acta. 1979, 62 (5): 1396-1400.
[72] 张金红.用微生物法进行手性化合物立体选择拆分的初步研究.南开大学报.1999,32:39-41.
[73] Madyastha K M, Reddy G C B, Nagarajappa H, Sridhar G R. N-Demethylation and Noxidation of thebaine, an isoquinoline alkaloid by Mucor piriformis. Indian J Chem Sect Borg chem. Incl. Med. Chem. 2000, 39:377-381.
[74] Kunz D A, Reddy G S, Vatvars A. Identification of transformation products arising from bacterial oxidation of codeine by Streptomyces griseus. Appl. Environ. Microb. 1985, 50:831-836.
[75] Zeitler H J, Niemer H. The microbial metabolism of colchicines. Hoppe-Seyler Z Physiol. Chem. 1969, 350:366-372.
[76] Rosazza J P, Kammer M, Youel L, Smith R V, Erhardt P W. Microbial models of mammalian metabofism: O-demethylation of papaverine. Xenobiotica 1977, 7:133-143.
[77] Herbert R. B: The biosynthesis of Secondary Metabolitas, Chapman and Hall Ltd; London, Mew York. 1981, 96-148.
[78] John P. Rosszza: Microbial Transformation of bioactive compound, Volume Ⅱ, CRC Press Jnc., Boca Raton. Florida. 1982, 67-90.
[79] Maureen R. Wilson, Winklet A. Gallmore P. Steroid transformation with Fusarium oxysporum Var. Cubense and Colletotrichum musae. Steroids 1999, 64:834-843.
[80] Mohammad A F. Microbial hydroxylation of progesterone with Acremonium stricture. FEMS Microbiology Lett. 2003, 222:183-186.
[81] Teresa Kolek. Biotransformation XL Ⅶ: transformations of 5-ene-steroids in Fusarium Culmorum culture. Journal of Steroid Biochemistry & Molecular Biology. 1999, 71:83-90.
[82] Shashi B, Mahato T Advances in microbial steroid biotransformation. Steroids 1997, 62:332-345.
[83] Antonino P. Biotransformation of progesterone by Chlopella Spp. Phytochemistry 1996, 42:685-688.
[84] Antonla J. Microbial hydroxylation of 13β-ethyl-4-gonene-3, 17-dione. Journal of molecular Catalysis B: Enzymatic. 1998, 5:385-387.
[85] Madyastha K M. Transformation of dehydroepiandrosterone and pregnenolone by mucor piriformis. Appl. Microb. Biotechn. 1995, 44:339-343.
[86] Ewa B. Biotransformation ⅩⅩⅪⅩ. Metabolism of Testosterone, Androstenedion, Progesterone and Testosterone Derivatves in Absidia coerulea Culture. Jounary of Steroid Biochem. Molec.Biol. 1996, 57:357-362.
[87] 叶敏.华蟾毒精和蟾毒灵的生物转化研究.北京大学博士论文.P107.
[88] Galal T M. Microbial metabolism of partheniol by Motor circinelloides. Phytochemistry 2002, 59:39-44.
[89] Clark A M. The use of microorganisms for the study of drug metabolism. Med. Res. Rev. 1985, 5:231-253.
[90] Dwight O. Collins. Biotransformation of squamuloosone by Curvularia lunata ATCC 12017. Phytochemistry 2001, 57: 377-383.
[91] Zhan J X, Guo Z, Guo D A. Microbial transformation of artemisinin by Cunninghamella echinulata and Aspergillus niger. Tetrahedron Lett. 2002, 43:4519-4521.
[92] Zhan J X, Guo Z, Guo D A. Microbial transformation of artemisinin by Mucor polymorphospotus and Aspergillus niger. J. Nat. Pord. 2002,65:1693-1695.
[93] Lin L N, Gui Q, Ye M, Guo D A. Cytotoxic Biotransformation Products from Triptonide by Aspergillus niger. Planta Med. 2003, 69:804-808.
[94] Lin L N, Zhan J X, Guo Z, Guo D A. Structural modifications of triptolide by cunninghamella blakesleana. Tetrahedron 2003, 59:4209-4213.
[95] Clark A M. Use of microorganisms for the study of drug metabolism: an update. Med. Res. Key. 1991, 11:473-501.
[96] Abourashed E A, Clark A M, Hufford C D. Microbial models of manmmalian metabolism ofxenobiotics: an updated review. Curr. Med. Chem. 1999, 6:359-374.
[97] Zhang D, Yang Y, Leakey J E, Cemiglia C E. Phasse Ⅰ and Ⅱ enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbial Lett. 1996, 138: 221-226.
[98] Adachi T, Saito M, Sasaki J, Karasawa Y, Omura S. Microbial hydroxylation of-eburnamonine by Mucor circinelooides and streptomyces violens. Chem. Pharm. Bull. 1993, 41:611-613.
[99] Lacroix I, Biton H, Azerad R. Microbial models of drug metabolism: microbial transformations of Trimegestone (RU 27987), a 3-keto-△~(4,9(10))-19-norsteroid drug. Bioorg. Med. Chem. 1999, 7:2329-2333.
[100] 刘磊,黄海华,孙路,钟大放.短刺小克银汉霉对维拉帕米的能力.中国药理学与毒理学杂志.2003,16:292-298.
[101] 黄海华,钟大放,杜宗敏.利用微生物转化模型研究苯丙哌林的代谢产物.中国药理学与毒理学杂志.2001,15:297-301.
[102] Jezequel S G. Microbial models of mammalian metabolism: uses and misuses. J. Mol Cata B: Enzymatic. 1998, 5:371-377.
[103] Holland H L. Microbial transformations. Curr. Opin. Chem. Biol. 1998, 2:77-84.
[104] Preisig C, Byng G. Application of mass spectrometry in screening for new biocatalysis. J. Mol. Cata. B: Enzyme. 2001, 11: 733-741.
[105] Demain L Arnold. Small bugs, big business: The economic power of the microbe. Biotechnology Advances 2000, 18(6):499-514.
[106] Rozzell J D. Commerical Scale Biocatalysis. Myths and Realities. Bioorg. Med. Chem. 1999, 7: 2253-2261.
[107] 王本祥.现代中药药理学[M]第1版.天津:天津科学技术出版社.1997,655.
[108] 赵敏华,吴清和.木香肠胃康胶囊对肠道功能的影响.中药材.2001,24(8):590-591.
[109] 冷恩仁,陈东风.木香对大鼠胃肠运动的影响及其机制探讨.中国中西医结合脾胃杂志.2000,8(4):236-238.
[110] 王永兵,王强,毛福林.木香的药效学研究.中国药科大学学报.2001,32(2):146-148.
[111] 刘月盈,汪循东,陈慧芝.复方木香注射液的药理作用研究.中成药研究.1983,5(6):27-29.
[112] 陈少夫,何凤云,李采权.木香对胃酸分泌、胃排空及胃泌素、生长抑素、胃动素水平的影响.中国中西医结合杂志.1994,14(7):406-408.
[113] 王元松,史国珍.中药对Ⅱ型糖尿病高血压症的疗效观察.中西医结合杂志.1992,20(5):45-46.
[114] 徐诺,巢志茂.月桂叶及其成分木香烯内酯对鼠肝脏中谷胱甘肽5-转移酶的诱导作用.国外医学·中医中药分册.1998,20(5):45-48.
[115] 陈先玉 魏银贵.木香微量元素分析.Journal of occupational Health and Demage.2004,19(1):34-36.
[116] Masatoshi T. Takao K. Dehydrocostuslactone as inhibitor of killing cytetaoxic. Biosci Biotechnol. Biochem. 1995, 59(11):2064-2065.
[117] Jae Y C, Park J, Yoo E S. Inhibitory effect of sesquiterpene lactone from Saussurea lappa on tumor necrosis factor α production in murine macriophage like cells. Plant Med. 1998, 64(7): 594-596.
[118] Chien Chen Hua, Chou Chenkung, Dea Shoudong. Active compounds from Saussurea lappa Clarke that suppress hepatitis B virus sueface antigengene expression in human hepatoma cell. Antiviral Res. 1995, 27(1-2):99-103.
[119] 山原条二.症予防剂.日本公开特许公报(A).平4-145076.1992-05-19.
[120] Okugawa H, Ueda R, Matsumoto K. Effect of dehydrocostuslactone and costunlide from Saussurea root on the central nervous system inmice. Phytomedicine 1996, 3(2):147-150.
[121] Kalsi P S, Kuemar S, Jawanda G S. Guaianolides from Saussurea lappa. Phytochemistry 1995, 40(6): 1713-1715.
[122] Dhillon R S, Kalsi P S, Singh W P. Guaianolides from Saussurea lappa. Phytochemistry 1987, 6(4):1209-1211.
[123] 杨辉,斜金伦,孙汉董.云木香化学成分研究Ⅰ.云南植物研究.1997,19(1):85-91.
[124] 杨敏.大耳叶风毛菊化学成分研究.兰州大学博士学位论文.P3
[125] Marte N, Rui M, Stefan G, Helen S E, Hostettmann K. New sesquiterpene lactones from the Portuguese liverwort Targionia lorbeeriana. Phytochemistry 1999, 50: 967-972.
[126] 贾忠建,李逾,石建功,王奇光.一个新愈创木内酯及其苷类的化学结构.化学学报.1991,49:1136-1141.
[127] Jacobsson U, Kumar V. Sesquiterpene lactones from michelia champaca. Phytochemistry 1995, 39(4): 839-843.
[128] Sanz J F, Falco E. Further new sesquiterpene lactones from Artemisia herba-alba subsp. Valentina. J. Nat. Product. 1990, 53(4):940-945.
[129] Sanz A, Juan F, Alberto Y, Miguel C. Sesquiterpene lactone from Artemia barrelieri. Phytochemistry 1991, 30(11): 3661-3668.
[130] Sanz J, Alberto J. Sesquiterpene lactones from Artemisia caerulescens subsp. Gargantea. Phytochemistry 1990, 29(9):2913-2917.
[131] Sanz J F, Castellano G, Marco Alerto. Sesquiterpene lactones from Artemisia herba-alba. Phytochemistry 1990, 29(2):541-545.
[132] 浙江药用植物志编写组.浙江药用植物志(下).杭州:浙江科学技术出版社.1980:1580-1582.
[133] 中国药典.二部.2000年版.2000:697-699.
[134] 王浴生,邓文龙,薛春生.中药药理与应用.第2版.人民卫生出版.1998:895-898.
[135] 王琰,王慕邹.姜黄属常用中药的研究进展.中国药学杂志.2001,36(2):80-83.
[136] 施广霞,于丽华,刘金友.β-榄香烯抗肿瘤作用的实验Ⅰ:β-榄香烯体外对L615白血病细胞直接作用的实验研究.大连医学院学报.1994,16(2):137-139.
[137] 杨骅,王仙平,郁琳琳.榄香烯抗癌作用与诱发肿瘤细胞凋亡.中华肿瘤杂志.1996,18(3):169-172.
[138] 吴万垠,罗云坚,程剑华.莪术油对小鼠肝癌细胞DNA作用的图像分析.中西医结合肝病杂志.1999,9(1):18-21.
[139] 崔秀云,李德山.β-榄香烯对RNA聚合酶活性的抑制及与DNA的结合.中国药理学报.1991,7(3):228-230.
[140] 卜长武,王东荣,郭文来.莪术对小白鼠免疫功能的影响.中国中医药信息杂志.1997,4(2):29-32.
[141] 钱震超,王大庆,黄金刚.瘤苗特异性主动免疫治疗及其机制研究.肿瘤生物治疗杂志.1999,2(2):125-126.
[142] 钱振超,王大庆,金成刚.瘤苗特异性主动免疫治疗及其机制的实验研究.肿瘤生物治疗杂志.1999,2(2):125-128.
[143] 陈红,邓德宁,范茜.莪术醇及莪术醇磷酸酯单钠对Ehrlich腹水癌细胞电位和钾离子通道的影响.首都医学院学报.1989,10(1):23.
[144] 贾静伟,胡佳辉。莪术油葡萄糖注射液治疗小儿病毒性肺炎21例疗效观察.龙江医药科学.1999,22(1):92-95.
[145] 满伟.莪术油药理研究及临床应用进展.时针国医国药.2000,11(7):663-664.
[146] 黄可新,陶正明,张安将.温莪术化学成分研究.中国中药杂志.2000,25(3):163-164.
[147] Takeshi Horiike, Masaaki Ohshiro, Masanori Karoyanagi. Biotransformation of the Germacrane type sesquiterpene curdione by suspensioncultured cells of Lonicera Japonica. Phytochemistry 1997, 44(4):627-632.
[148] 戴方澜.中国真菌总汇.科学出版社1989.
[149] 陈士榆.昆虫知识.1986,(3):133-135.
[150] 国家中药医药管理局《中华本草》委员会,《中华本草》第一卷上海科学科技出版社.1995,495-498.