山胡椒抗肿瘤转移化学成分研究
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摘要
山胡椒[Lindera glauca var.(Siebold et Zucc.)Blume],是我国的传统中药,应用历史悠久,属樟科(Lauraceae)山胡椒属(Lindera)植物。我国长江中下游、秦岭、淮河以南17个省区均有山胡椒分布,资源极为丰富。山胡椒味辛、大热、无毒,主治心腹痛,中冷,破滞等症。现代药理学研究表明山胡椒具有细胞毒、抗菌和抗病毒等活性。
本文以发现新生物活性成分为目的,对山胡椒进行抗肿瘤转移作用研究发现,95%乙醇提取物具有明确的抗人乳腺癌细胞(MDA-MB-231)的趋化迁移作用,在浓度30μg.ml-1下,抑制率达到57.69%。本课题对山胡椒开展了抗肿瘤转移化学成分研究,采用溶剂萃取、常压硅胶柱色谱和凝胶柱色谱分离,制备高效液相色谱纯化,从山胡椒的正丁醇和乙酸乙酯层提取物中共分得10个化合物,属于生物碱和单萜类化合物,进一步利用MS、1H.NMR、13C-NMR、HMBC、HSQC等有机波谱学方法对其化学结构进行了鉴定,分别为樟苍碱(1),N-甲基樟苍碱(2),瑞枯灵(3),紫堇碱(4),N-反式阿魏酸酪酰胺(5),N-顺式阿魏酸酪酰胺(6),芒籽香碱(7),降异紫堇定碱(8),[9,9,9-2H3]-(1S*,3S*,4S*, 8S*)-ρ-Menthane-3,8-diol(9),[9,9,9-2H3]-(1S*,3R*,4S*,8S*)-ρ-Menthane-3,8-diol(10)。其中化合物9和10为首次从该属植物中分离得到,化合物3为首次从该植物中分离得到。
本文进一步以Transwell趋化实验方法对山胡椒的各提取部位和化合物进行了抗肿瘤转移活性的筛选。实验结果表明化合物1,2,4,5,7和9均有明确的抗肿瘤转移作用,其中化合物l,4和5的抗肿瘤转移活性较强,化合物l在浓度4μg.ml-1下对人乳腺癌细胞MD-MBA-231趋化抑制率达到70.7%。
As a traditional Chinese medicine, the application of Lindera glauca has a long history, which is a plant of Lauraceae Lindera. The resources of Lindera glauca are very rich, which are widely distributed in 17 provinces in China's Yangtze River, Qinling Mountains and south of the Huaihe River. As a Chinese folk medicine, Lindera glauca has the properties of removing cold, preventing cardiovascular and cerebrovacular diseases and so on. In addition, Mordern pharmacology research suggests Lindera glauca has the activities of cytotoxic, anti-bacterial and anti-virus activity.
In order to search the new bioactive constituents from natural source, the anti-tumor metastatic screening experiment was under taken. The 95% ethanol extract revealed significant anti-tumor metastatic effect in MDA-MB-231 cell lines, and the value of anti-tumor metastatic inhibition ratio was 57.69% at the concentration of 30μg·ml-1. We started to study the bioactive chemical consitituents from Lindera glauca. By repeated column chromatography, including silica gel, toyopearl HW-40 and preparative HPLC,10 compounds were isolated from extract of Lindera glauca. By using MS,1H-NMR, 13C-NMR, HMBC, HSQC spectra analysis, the structures of ten compounds were identified as follows:laurotetanine (1), N-methyllaurotetanine (2), reticuline (3), pallidine (4), N-trans-feruloyltyramine (5), N-cis-feruloyltyramine (6), atheroline (7), norisosocorydine (8), [9,9,9-2H3]-(1S*,3S*,4S*,8S*)-p-menthane-3, 8-diol (9), [9,9,9-2H3]-(1S*,3R*,4S*,8S*)-p-menthane-3,8-diol (10). Compounds 9 and 10 were isolated from Lindera genus for the first time and compound 3 was isolated from this plant for the first time.
The anti-tumor metastatic assay was applied to evaluate the solated compounds. Compounds 1,2,4,5,7 and 9 showed positive anti-tumor metastatic activities, and compounds 1,4, and 5 showed significant anti-tumor metastatic activities. At the concentration of 4μg-ml-1, the value of metastatic inhibition ratio of compound 1 was 70.7% in MDA-MB-231 cell lines.
本文以发现新生物活性成分为目的,对山胡椒进行抗肿瘤转移作用研究发现,95%乙醇提取物具有明确的抗人乳腺癌细胞(MDA-MB-231)的趋化迁移作用,在浓度30μg.ml-1下,抑制率达到57.69%。本课题对山胡椒开展了抗肿瘤转移化学成分研究,采用溶剂萃取、常压硅胶柱色谱和凝胶柱色谱分离,制备高效液相色谱纯化,从山胡椒的正丁醇和乙酸乙酯层提取物中共分得10个化合物,属于生物碱和单萜类化合物,进一步利用MS、1H.NMR、13C-NMR、HMBC、HSQC等有机波谱学方法对其化学结构进行了鉴定,分别为樟苍碱(1),N-甲基樟苍碱(2),瑞枯灵(3),紫堇碱(4),N-反式阿魏酸酪酰胺(5),N-顺式阿魏酸酪酰胺(6),芒籽香碱(7),降异紫堇定碱(8),[9,9,9-2H3]-(1S*,3S*,4S*, 8S*)-ρ-Menthane-3,8-diol(9),[9,9,9-2H3]-(1S*,3R*,4S*,8S*)-ρ-Menthane-3,8-diol(10)。其中化合物9和10为首次从该属植物中分离得到,化合物3为首次从该植物中分离得到。
本文进一步以Transwell趋化实验方法对山胡椒的各提取部位和化合物进行了抗肿瘤转移活性的筛选。实验结果表明化合物1,2,4,5,7和9均有明确的抗肿瘤转移作用,其中化合物l,4和5的抗肿瘤转移活性较强,化合物l在浓度4μg.ml-1下对人乳腺癌细胞MD-MBA-231趋化抑制率达到70.7%。
As a traditional Chinese medicine, the application of Lindera glauca has a long history, which is a plant of Lauraceae Lindera. The resources of Lindera glauca are very rich, which are widely distributed in 17 provinces in China's Yangtze River, Qinling Mountains and south of the Huaihe River. As a Chinese folk medicine, Lindera glauca has the properties of removing cold, preventing cardiovascular and cerebrovacular diseases and so on. In addition, Mordern pharmacology research suggests Lindera glauca has the activities of cytotoxic, anti-bacterial and anti-virus activity.
In order to search the new bioactive constituents from natural source, the anti-tumor metastatic screening experiment was under taken. The 95% ethanol extract revealed significant anti-tumor metastatic effect in MDA-MB-231 cell lines, and the value of anti-tumor metastatic inhibition ratio was 57.69% at the concentration of 30μg·ml-1. We started to study the bioactive chemical consitituents from Lindera glauca. By repeated column chromatography, including silica gel, toyopearl HW-40 and preparative HPLC,10 compounds were isolated from extract of Lindera glauca. By using MS,1H-NMR, 13C-NMR, HMBC, HSQC spectra analysis, the structures of ten compounds were identified as follows:laurotetanine (1), N-methyllaurotetanine (2), reticuline (3), pallidine (4), N-trans-feruloyltyramine (5), N-cis-feruloyltyramine (6), atheroline (7), norisosocorydine (8), [9,9,9-2H3]-(1S*,3S*,4S*,8S*)-p-menthane-3, 8-diol (9), [9,9,9-2H3]-(1S*,3R*,4S*,8S*)-p-menthane-3,8-diol (10). Compounds 9 and 10 were isolated from Lindera genus for the first time and compound 3 was isolated from this plant for the first time.
The anti-tumor metastatic assay was applied to evaluate the solated compounds. Compounds 1,2,4,5,7 and 9 showed positive anti-tumor metastatic activities, and compounds 1,4, and 5 showed significant anti-tumor metastatic activities. At the concentration of 4μg-ml-1, the value of metastatic inhibition ratio of compound 1 was 70.7% in MDA-MB-231 cell lines.
引文
[1]钱学射,肖正春.山胡椒的研究与利用.商业部南京野生植物综合利用研究所.
[2]崔鸿宾.山胡椒属系统的研究[J].植物分类学报,1987,25(3)：167-171.
[3]张朝凤.乌药与鼎湖钓樟的化学成分及抗HIV-l整合酶活性研究[D].沈阳：沈阳药科大学,2002.
[4]雷载权.中药学[M].上海科学技术出版社,1995：164
[5]中国药材公司.中国中药资源志要[J].北京：科学出版社,1994：287.
[6]余德贵.山胡椒的药理作用[J].基层中药杂志,1996,10(4)：41.
[7]张茂江.乌药的临床应用[J].四川中医,1994,2(5)：18.
[8]Huang Ray-ling, Chen chien-chich, Huang Yu-lin, et al. Antitumor effect of d-dicentrine from the root of Lindera megaphylla [J]. Planta Media, 1998,64:212-213.
[9]Mutsuo Kozuka, Masahiko shibaka wa, Katsumi Yohimura, et al. Alkaloids from Lindera glauca, Lindera erythrocarpa and Lindera citriodora [J]. J Net Prod,1984,47(6):1066.
[10]Kozuka M, M Takeuchi and T Sawada. Alkaloids from Lindera strychmifolia [J]. J Nat Prod,1984,47(6):1063.
[11]潼尺信夫.Lindera属の成方研究[J].生药学杂志(日),1984,38(2)：194-197.
[12]Kazuhiko Ichino, Hitoshi Tanaka, Kazuolto. Studies on the flavonoid components of Lindera umbellata var. Membranacea(Maxim)Momi Yama [J]. Chem Pharm Bull,1989,37(4):944-947.
[13]Kazuhiko Ichino. Two flavonoids from two Lindera umbellata varieties [J]. Phytochemistry,1989,28(3):955-956.
[14]Kazuhiko Ichino, Hitoshi Tanaka, KazuIto. A new flavanone, neolinderatone from Lindera umbellata var. Iancea [J]. Chem Pharm Bull,1989,37(5): 4126-4127.
[15]Hirixi Shimomura, Yutaka Saslida, Yoshihiro, et al. Chalone derivative from the bark of Lindera umbellate [J]. Phytochemistry,1998,27(12):3937-3939.
[16]肖培根.中药志(第一卷)[M].化学工业出版社,2002：232.
[17]罗永明,黄璐,汪平,等.山橿地上、地下部分挥发油成分的研究[J].中国中药杂志,2004,39(4)：309.
[18]Hayashi Nanao, Komae Hisashi. Chemistry and distribution of sesquiterene. Furan in lauraceae[J].Biochem Syst Ecol,1980,8(4):381-383.
[19]桂新,王峥涛,徐路珊,等.乌药的化学成分及药理作用[J].中国野生植物资源,2002,18(3)：5.
[20]陈随清,左艇.河南山胡椒属植物资源及其药理、化学及应用研究[J].河南中医学院学报,2005,20(3)：25.
[21]张朝凤,王峥涛.山胡椒属药用植物的研究进展[J].沈阳药科大学学报,2000,17(3)：230.
[22]赵利琴.山胡椒属萜类及其生物活性研究进展[J].时珍国医国药,2006,17(2)： 171.
[23]罗镭，田景奎,杨世林.山胡椒属药用植物化学成分研究进展[J].亚太传统医药,2007,3(10)：57.
[24]杨得坡,王发松,任三香,等.山胡椒果挥发油的化学成分与抗真菌活性.[J].中药材,1999,22(6)：295-298.
[25]Chen WY, Ko FN, Wu YC, et al. Vasorrelaxing effect in rat thoracic aorta caused by laurotetanine isolated from Litsea cubeba Persoon [J]. J Pharm Phammcol,1994,46:380-382.
[26]赵奇志,赵毅民.阿朴菲类生物碱生物活性研究进展[J].天然产物研究与开发,2006,18：316-324.
[27]Boustie J, Stigliani JL, Montanha J, et al. Antipoliovirus structure-activity relationships of some aporphine alkaloids. J Nat Prod,1998,61:480-484.
[28]Tanaka T, Bai Z, Srinoulprasert Y, Yang BG., Hayasaka H, Miyasaka M. Chemokines in tumor progression and metastasis [J]. Cancer Sci.2005,96: 317-322.
[29]赵奇志,赵毅民,王克军.狭叶山胡椒根中的生物碱成分.[J].药学学报,2005,40(10)：931.
[30]李海明,白虹,李巍,等.玉竹化学成分研究[J].食品与药品,2010,12(3)：102.
[31]陈华,阿吉艾克拜尔·艾萨,李援朝,等.短叶假木贼中化学成分的分离和结构鉴定[J].天然产物研究与开发,2006,18：958.
[32]Pavel Kocovsky, Ghafoor Ahmed, Jiri Srogl, et al. New Lewis-Acidic Molybdenum(Ⅱ) and Tungsten(Ⅱ) Catalysts for Intramolecular Carb onyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal [J]. J. Org. Chem.1999,64:2765.
[33]高光耀,陈四保,王立为,等.狭序唐松草化学成分的研究(Ⅲ)[J].中草药,2000,31(5)：324.
[34]Richard H. A. M. Janssen, Peter Wijkens, Cor Kruk, et al. Assignments of 1H and 13C NMR resonances of some isoquinoline Alkaloids [J]. Phytochemlstry, 1990,29(10):3331.
[35]Yuh-Chwen Chang, Chung-Yi Chen, Fang-Rong Chang, et al. Alkaloids from Lindera glauca [J]. Journal of the Chinese Chemical Society,2001,48:811.
[36]朱超兰,杨培明.豆豉姜的化学成分分离和结构鉴定[J].中国医药工业杂志,2007,38(8)：558.
[37]Marcia L.R. Ferreira, Inara C. de Pascoli, Isabele R. Nascimento, et al. Aporphine and bisaporphine alkaloids from Aristolochia lagesiana var. intermedia [J]. Phytochemistry,2010,71:469.
[38]Pavel Kocovsky, Ghafoor Ahmed, Jifi Srogl, et al. New Lewis-Acidic Molybdenum(Ⅱ) and Tungsten(Ⅱ) Catalysts for Intramolecular Carb onyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal [J]. J. Org. Chem.1999,64:2765.
[1]崔鸿宾.山胡椒属系统的研究[J].植物分类学报,1987,25(3)：167-171.
[2]罗镭,田景奎,杨世林.山胡椒属药用植物化学成分研究进展[J].亚太传统医药,2007,3(10)：57-60.
[3]陈随清,左艇.河南山胡椒属植物资源及其药理、化学及应用研究[J].河南中医学院学报,2005,20(18)：25-27.
[4]张朝凤,王峥涛.山胡椒属药用植物的研究进展[J].沈阳药科大学学报,2000,17(3)：230-234.
[5]李庆林.乌药提取物的镇痛抗炎作用研究[J].中药材,1997,20(12)：523-524.
[6]Huang Ray-ling, Chen Chien-chich, Huang Yu-lin, et al. Antitumor effect of d-dicentrine from the root of Lindera megaphylla [J]. Planta Medica,1998,64: 212-213.
[7]Mutsuo Kozuka, Masahiko Shibakawa, Katsumi Yohimura, et al. Alkaloids from Lindera glauca, Lindera erythrocarpa and Lindera citriodora [J]. J Nat Prod,1984,47(6):1066-1068.
[8]张均增,方起程.山橿化学成分的研究[J].中草药,1994,25(11)：565-568.
[9]Mutso Kozuka, Mosa Yuki, Yoshi Kawa, et al. Alkaloid from Lindera strychnifolia [J]. J Nat Prod,1984,47(6):1063-1065.
[10]Chen Chien-chih, Lin Chuan-fwu, Huang Yu-ling, et al. Bioactive constituents from the flower buds and peducles on Lindera megaphylla [J]. J Nat Prod, 1995,58(9):1423-1425.
[11]Chou Chen-jen, Lin Lie-chwen, Chen Kuo-tunget, Nor-thalifoline. A new isoquinolene alkaloid from the spedicels of Lindera megaphylla [J]. J Nat Prod, 1994,57(6):689-694.
[12]Gui Xin CHOU, Zheng Tao WANG, Isoquinoline Alkaloides from Lindera [J]. aggregate. Chin J Nat Med,2005, (3)5:272-275.
[13]赵奇志,赵毅民.狭叶山胡椒根中的生物碱成分[J].药学学报,2005,40(10)：931-934.
[14]Kazuhiko Ichino, Hitoshi Tanaka, Kazuo Ito. Studies on the flavonoid components of Lindera umbellata var. Membranacea (Maxim) Momi Yama [J]. Chem Pharm Bull,1989,37(4):944-947.
[15]Kazuhiko Ichino. Two flavonoids from two Lindera umbellata varieties [J]. Phytochemistry,1989,28(3):955-956.
[16]Kazuhiko Ichino, Hitoshi Tanaka, KazuIto. Anew flavanone, neolinderatone from Lindera umbellata var. Iancea [J]. Chem Pharm Bull,1989,37(5): 4126-4127.
[17]潼尺信夫.Lindera属の成方研究[J].生药学杂志(日),1984,38(2)：194-197.
[18]Hirixi Shimomura, Yutaka Saslida, Yoshihiro, et al. Chalone derivative from the bark of Lindera umbellata [J]. Phytochemistry,1998,27(12):3937-3939.
[19]Park Jong-cheol, Yu Young-beob, Lee Jong-ho, et al. Isolation and stucture elucidation of flavonoid glycosides from Lindera obtusiloba Bl [J]. Hanguk Yongyang Sikyong Hakhochi,1996,25(1):76-79.
[20]Park Jong-cheol, Park Ju-gwan, Kim Jong-hong, et al. Isolation of kaempferol glycoside from Lindera sericea and anti-inflammatory [J]. Hanguk Yangyang Sikyong Hakhochi,1996,25(3):519-552.
[2l]龙康侯,苏镜娱,曾陇梅,等.萜类化学[M].北京高等教育出版社,1984.
[22]谭仁祥.植物成分分析[M].北京：科学出版社,2000：386.
[23]高锦明.植物化学[M].北京：科学出版社,2003：217.
[24]匡海学.中药化学[M].北京：中国中医药出版社,2003：181.
[25]徐任生.天然产物化学[M].北京：科学出版社,2004：166.
[26]刘立鼎,顾静文,陈京达.山胡椒叶子化学成分及其应用[J].江西科学,1992,10(1)：38.
[27]杨得坡,王发松,任三香,等.山胡椒果挥发油的化学成分与抗真菌活性….中药材,1999,22(6)：295.
[28]俞志雄,杨贤辉,王岳峰,等.狭叶山胡椒叶油的化学成分[J].江西农业大学学报,199l,13(1)：40.
[29]魏圣淑,刘向前,吴世旭,等.韩国药用植物黄梅木果实挥发油成分的GC-MS研究[J].中草药,2004,35(10)：1097.
[30]杜志谦,夏华玲,江海肖,等.乌药挥发油化学成分的分析[J].中草药,2003,34(4)：308.
[31]罗永明,黄璐琦,汪平,等.山橿地上、地下部分挥发油成分的研究[J].中国药学杂志,2004,39(4)：307.
[32]周继斌,范明,周文波.乌药挥发油化学成分测定[J].中国野生植物资源,18(2)： 48.
[33]周继斌,翁水旺,范明,等.乌药块根及根、茎挥发油成分的测定[J].中国野生植物资源,19(3)：45.
[34]杨得坡,王发松,彭劲甫,等.香叶树叶精油的GC-MS分析与抑菌活性[J].中药材,1999,22(3)：128.
[35]王发松,杨得坡,任三香,等.香叶树果挥发油的化学成分和抗菌活性研究[J].天然产物研究与开发,1999,1](6)：1.
[36]Niwa M, Iguchi M, Yamamua. The structure of C17-obtusilactone and two C21-obtusiliactone [J]. Tetrahedron Lett,1975:4395
[37]Katsura Seki, Takayuki Sasaki, Kazuo Haga, et al. Two methoxybutanolides from Lindera glauca [J]. Phytochemistry,1994,36(4):949-951
[38]Katura Seki, Takayuki Sasaki, Sutoshi wano, et al. Linderanolide and isolinderanolides, ten butanolides from Lindera glauca [J]. Phytochemistry, 1984,40(4):1175-1181.
[39]Jone anderson, Wenwen Ma, David LSmith, et al. Biologically active y-lactone and methylketoalkene from Lindera benzon [J]. J Nat Prod,1992, 55(1):71-83.
[40]张朝凤,孙启时,王峥涛,等.乌药叶化学成分研究[J].中国中药杂志,2001,26(11)：765.
[41]Kouno I, HiraiA, Fukusbige A, et al. New eudesmane sesquiterpenes from the root of Lindera strychnifolia [J] Nat Prod,2001,64(3):286.
[42]Zhang CF, Norio Nakamura, Sup inya Tewtrakul, et al. Sesquiterpenes and Alkaloids from Lindera chunii and their Inhibitory Activities against H IV-1 Integrase [J]. Chem, Pharm. Bull,2002,50(9):1195.
[43]Jian BL, YiD, WeiMl. A new sesquiterpene from the roots of Lindera Strychnifolia [J]. Chinese Chermical Letters,2002,13(10):965.
[44]Chou GX, Norio Nakamura, Ma CM, et al. Seven New Sesquiterpene Lactones from Lindera aggregata [J]. Journal of China Pharmaceutical University,200, 31(5):339.
[45]Isao Kouno, Asuka Hirai, Jiang ZH, et al. Bisequiterpenoid from the root of Lindera strychnifolia [J]. Phytochemistry,1997,46(7):1283.
[46]Hayashi Nanao, Komae Hisashi. Chemistry and distribution of sesquiterene. Furan in lauraceae [J]. Biochem Syst Ecol,1980,8(4):381-383.
[47]刘立鼎,陈京达,兰胜贵.山胡椒果实化学成分研究及应用实验[J].植物学报,1982,24(3)：252-258.
[48]Kazuhiko Ichino, Hitoshi Tanako, Kszuo Ito. A lignon from Lindera praecox [J]. Phytochemistry,1988,27(6):1096.
[49]Nobuhisa Ezaki, Masahide Kato, Nobuo Takizama, et al. Pharmacological studies on Lindera umbellata RumsⅣ[J]. Planta Medica,1985, (51):34-38.
[50]Yoshihiro Mimaki, Aiko Kameyama, Yutaka sashida, et al. A novel hexahydrodibenzofuran derivative with potent inhibitory activity on melanin biosynthesis of cultured B-16 melanoma cell from Lindera umbellate bark [J]. Chem Pharm Bull,1995,43(5):893-895.
[51]雷载权.中药学[M].上海：上海科学技术出版社,1995：164.
[52]张茂江.乌药的临床应用[J].四川中医,1994,12(5)：18.
[53]中国药材公司.中国中药资源志要[M].北京：科学出版社,1994：287.
[54]张树云.毛黑壳楠树皮中荷包牡丹碱的提取[J].中草药,1994.
[55]余德贵.山胡椒的药理作用[J].基层中药杂志,1996,10(4)：41.
[56]钱学射,肖正春.山胡椒的研究与利用.商业部南京野生植物综合利用研究所.
[57]张天明,胡珍姣,欧黎红.三种中草药抗病毒的实验研究[J].辽宁中医杂志,1994,21(11)：523-524.
[58]张小云,覃文庆,喻连香.山胡椒挥发油的提取及其抑菌活性研究[J].现代生物医学进展,2010,10(1)：133-136.
[59]Kang JJ, Cheng YW. Effects of boldine on mouse diaphragm and sarcoplasmic reticulum vesicles isolated from skeletal muscle [J]. Planta Med,1998,64: 18-21.
[60]Speisky H, Squella JA, Ntmez-Vergara LJ. Activity of boldine on rat ileum. Planta Med,1991,57:519-522.
[61]赵利琴.山胡椒属萜类及其生物活性研究进展.时珍国医国药,2006,17(2)： 171-174.
[62]桂新,王峥涛,徐珞珊,等.乌药化学成分及药理作用[J].中国野生植物资源,1998,18(3)：5.
[63]KobayashiW. miyase T, SanoM, Umehara K, et al. Prolyl endopep tidase inhibitors from the roots ofLindera strychnifolia F. Vill [J]. Biol Pharm Bull, 2002,25(8):1049.
[65]Li YM, Ohno, Minatoguchi S, Fukuda K, et al. Extracts from the roots of Lindera strychifolia induces apop tosis in lung cancer cells and prolongs survival of tumor-bearing mice [J]. Am J Cjin Med,2003,31(6):857.
[66]李智.乌药应用经验[J].江西中西药,1994,25(4)：63.
[67]彭墩.乌药治疗泌尿系统结石[J].甘肃中医,1994,7(5)：34.
[68]河南省卫生厅.河南省药品标准[S].郑州：河南科学技术出版社,1984：157.
[2]崔鸿宾.山胡椒属系统的研究[J].植物分类学报,1987,25(3)：167-171.
[3]张朝凤.乌药与鼎湖钓樟的化学成分及抗HIV-l整合酶活性研究[D].沈阳：沈阳药科大学,2002.
[4]雷载权.中药学[M].上海科学技术出版社,1995：164
[5]中国药材公司.中国中药资源志要[J].北京：科学出版社,1994：287.
[6]余德贵.山胡椒的药理作用[J].基层中药杂志,1996,10(4)：41.
[7]张茂江.乌药的临床应用[J].四川中医,1994,2(5)：18.
[8]Huang Ray-ling, Chen chien-chich, Huang Yu-lin, et al. Antitumor effect of d-dicentrine from the root of Lindera megaphylla [J]. Planta Media, 1998,64:212-213.
[9]Mutsuo Kozuka, Masahiko shibaka wa, Katsumi Yohimura, et al. Alkaloids from Lindera glauca, Lindera erythrocarpa and Lindera citriodora [J]. J Net Prod,1984,47(6):1066.
[10]Kozuka M, M Takeuchi and T Sawada. Alkaloids from Lindera strychmifolia [J]. J Nat Prod,1984,47(6):1063.
[11]潼尺信夫.Lindera属の成方研究[J].生药学杂志(日),1984,38(2)：194-197.
[12]Kazuhiko Ichino, Hitoshi Tanaka, Kazuolto. Studies on the flavonoid components of Lindera umbellata var. Membranacea(Maxim)Momi Yama [J]. Chem Pharm Bull,1989,37(4):944-947.
[13]Kazuhiko Ichino. Two flavonoids from two Lindera umbellata varieties [J]. Phytochemistry,1989,28(3):955-956.
[14]Kazuhiko Ichino, Hitoshi Tanaka, KazuIto. A new flavanone, neolinderatone from Lindera umbellata var. Iancea [J]. Chem Pharm Bull,1989,37(5): 4126-4127.
[15]Hirixi Shimomura, Yutaka Saslida, Yoshihiro, et al. Chalone derivative from the bark of Lindera umbellate [J]. Phytochemistry,1998,27(12):3937-3939.
[16]肖培根.中药志(第一卷)[M].化学工业出版社,2002：232.
[17]罗永明,黄璐,汪平,等.山橿地上、地下部分挥发油成分的研究[J].中国中药杂志,2004,39(4)：309.
[18]Hayashi Nanao, Komae Hisashi. Chemistry and distribution of sesquiterene. Furan in lauraceae[J].Biochem Syst Ecol,1980,8(4):381-383.
[19]桂新,王峥涛,徐路珊,等.乌药的化学成分及药理作用[J].中国野生植物资源,2002,18(3)：5.
[20]陈随清,左艇.河南山胡椒属植物资源及其药理、化学及应用研究[J].河南中医学院学报,2005,20(3)：25.
[21]张朝凤,王峥涛.山胡椒属药用植物的研究进展[J].沈阳药科大学学报,2000,17(3)：230.
[22]赵利琴.山胡椒属萜类及其生物活性研究进展[J].时珍国医国药,2006,17(2)： 171.
[23]罗镭，田景奎,杨世林.山胡椒属药用植物化学成分研究进展[J].亚太传统医药,2007,3(10)：57.
[24]杨得坡,王发松,任三香,等.山胡椒果挥发油的化学成分与抗真菌活性.[J].中药材,1999,22(6)：295-298.
[25]Chen WY, Ko FN, Wu YC, et al. Vasorrelaxing effect in rat thoracic aorta caused by laurotetanine isolated from Litsea cubeba Persoon [J]. J Pharm Phammcol,1994,46:380-382.
[26]赵奇志,赵毅民.阿朴菲类生物碱生物活性研究进展[J].天然产物研究与开发,2006,18：316-324.
[27]Boustie J, Stigliani JL, Montanha J, et al. Antipoliovirus structure-activity relationships of some aporphine alkaloids. J Nat Prod,1998,61:480-484.
[28]Tanaka T, Bai Z, Srinoulprasert Y, Yang BG., Hayasaka H, Miyasaka M. Chemokines in tumor progression and metastasis [J]. Cancer Sci.2005,96: 317-322.
[29]赵奇志,赵毅民,王克军.狭叶山胡椒根中的生物碱成分.[J].药学学报,2005,40(10)：931.
[30]李海明,白虹,李巍,等.玉竹化学成分研究[J].食品与药品,2010,12(3)：102.
[31]陈华,阿吉艾克拜尔·艾萨,李援朝,等.短叶假木贼中化学成分的分离和结构鉴定[J].天然产物研究与开发,2006,18：958.
[32]Pavel Kocovsky, Ghafoor Ahmed, Jiri Srogl, et al. New Lewis-Acidic Molybdenum(Ⅱ) and Tungsten(Ⅱ) Catalysts for Intramolecular Carb onyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal [J]. J. Org. Chem.1999,64:2765.
[33]高光耀,陈四保,王立为,等.狭序唐松草化学成分的研究(Ⅲ)[J].中草药,2000,31(5)：324.
[34]Richard H. A. M. Janssen, Peter Wijkens, Cor Kruk, et al. Assignments of 1H and 13C NMR resonances of some isoquinoline Alkaloids [J]. Phytochemlstry, 1990,29(10):3331.
[35]Yuh-Chwen Chang, Chung-Yi Chen, Fang-Rong Chang, et al. Alkaloids from Lindera glauca [J]. Journal of the Chinese Chemical Society,2001,48:811.
[36]朱超兰,杨培明.豆豉姜的化学成分分离和结构鉴定[J].中国医药工业杂志,2007,38(8)：558.
[37]Marcia L.R. Ferreira, Inara C. de Pascoli, Isabele R. Nascimento, et al. Aporphine and bisaporphine alkaloids from Aristolochia lagesiana var. intermedia [J]. Phytochemistry,2010,71:469.
[38]Pavel Kocovsky, Ghafoor Ahmed, Jifi Srogl, et al. New Lewis-Acidic Molybdenum(Ⅱ) and Tungsten(Ⅱ) Catalysts for Intramolecular Carb onyl Ene and Prins Reactions. Reversal of the Stereoselectivity of Cyclization of Citronellal [J]. J. Org. Chem.1999,64:2765.
[1]崔鸿宾.山胡椒属系统的研究[J].植物分类学报,1987,25(3)：167-171.
[2]罗镭,田景奎,杨世林.山胡椒属药用植物化学成分研究进展[J].亚太传统医药,2007,3(10)：57-60.
[3]陈随清,左艇.河南山胡椒属植物资源及其药理、化学及应用研究[J].河南中医学院学报,2005,20(18)：25-27.
[4]张朝凤,王峥涛.山胡椒属药用植物的研究进展[J].沈阳药科大学学报,2000,17(3)：230-234.
[5]李庆林.乌药提取物的镇痛抗炎作用研究[J].中药材,1997,20(12)：523-524.
[6]Huang Ray-ling, Chen Chien-chich, Huang Yu-lin, et al. Antitumor effect of d-dicentrine from the root of Lindera megaphylla [J]. Planta Medica,1998,64: 212-213.
[7]Mutsuo Kozuka, Masahiko Shibakawa, Katsumi Yohimura, et al. Alkaloids from Lindera glauca, Lindera erythrocarpa and Lindera citriodora [J]. J Nat Prod,1984,47(6):1066-1068.
[8]张均增,方起程.山橿化学成分的研究[J].中草药,1994,25(11)：565-568.
[9]Mutso Kozuka, Mosa Yuki, Yoshi Kawa, et al. Alkaloid from Lindera strychnifolia [J]. J Nat Prod,1984,47(6):1063-1065.
[10]Chen Chien-chih, Lin Chuan-fwu, Huang Yu-ling, et al. Bioactive constituents from the flower buds and peducles on Lindera megaphylla [J]. J Nat Prod, 1995,58(9):1423-1425.
[11]Chou Chen-jen, Lin Lie-chwen, Chen Kuo-tunget, Nor-thalifoline. A new isoquinolene alkaloid from the spedicels of Lindera megaphylla [J]. J Nat Prod, 1994,57(6):689-694.
[12]Gui Xin CHOU, Zheng Tao WANG, Isoquinoline Alkaloides from Lindera [J]. aggregate. Chin J Nat Med,2005, (3)5:272-275.
[13]赵奇志,赵毅民.狭叶山胡椒根中的生物碱成分[J].药学学报,2005,40(10)：931-934.
[14]Kazuhiko Ichino, Hitoshi Tanaka, Kazuo Ito. Studies on the flavonoid components of Lindera umbellata var. Membranacea (Maxim) Momi Yama [J]. Chem Pharm Bull,1989,37(4):944-947.
[15]Kazuhiko Ichino. Two flavonoids from two Lindera umbellata varieties [J]. Phytochemistry,1989,28(3):955-956.
[16]Kazuhiko Ichino, Hitoshi Tanaka, KazuIto. Anew flavanone, neolinderatone from Lindera umbellata var. Iancea [J]. Chem Pharm Bull,1989,37(5): 4126-4127.
[17]潼尺信夫.Lindera属の成方研究[J].生药学杂志(日),1984,38(2)：194-197.
[18]Hirixi Shimomura, Yutaka Saslida, Yoshihiro, et al. Chalone derivative from the bark of Lindera umbellata [J]. Phytochemistry,1998,27(12):3937-3939.
[19]Park Jong-cheol, Yu Young-beob, Lee Jong-ho, et al. Isolation and stucture elucidation of flavonoid glycosides from Lindera obtusiloba Bl [J]. Hanguk Yongyang Sikyong Hakhochi,1996,25(1):76-79.
[20]Park Jong-cheol, Park Ju-gwan, Kim Jong-hong, et al. Isolation of kaempferol glycoside from Lindera sericea and anti-inflammatory [J]. Hanguk Yangyang Sikyong Hakhochi,1996,25(3):519-552.
[2l]龙康侯,苏镜娱,曾陇梅,等.萜类化学[M].北京高等教育出版社,1984.
[22]谭仁祥.植物成分分析[M].北京：科学出版社,2000：386.
[23]高锦明.植物化学[M].北京：科学出版社,2003：217.
[24]匡海学.中药化学[M].北京：中国中医药出版社,2003：181.
[25]徐任生.天然产物化学[M].北京：科学出版社,2004：166.
[26]刘立鼎,顾静文,陈京达.山胡椒叶子化学成分及其应用[J].江西科学,1992,10(1)：38.
[27]杨得坡,王发松,任三香,等.山胡椒果挥发油的化学成分与抗真菌活性….中药材,1999,22(6)：295.
[28]俞志雄,杨贤辉,王岳峰,等.狭叶山胡椒叶油的化学成分[J].江西农业大学学报,199l,13(1)：40.
[29]魏圣淑,刘向前,吴世旭,等.韩国药用植物黄梅木果实挥发油成分的GC-MS研究[J].中草药,2004,35(10)：1097.
[30]杜志谦,夏华玲,江海肖,等.乌药挥发油化学成分的分析[J].中草药,2003,34(4)：308.
[31]罗永明,黄璐琦,汪平,等.山橿地上、地下部分挥发油成分的研究[J].中国药学杂志,2004,39(4)：307.
[32]周继斌,范明,周文波.乌药挥发油化学成分测定[J].中国野生植物资源,18(2)： 48.
[33]周继斌,翁水旺,范明,等.乌药块根及根、茎挥发油成分的测定[J].中国野生植物资源,19(3)：45.
[34]杨得坡,王发松,彭劲甫,等.香叶树叶精油的GC-MS分析与抑菌活性[J].中药材,1999,22(3)：128.
[35]王发松,杨得坡,任三香,等.香叶树果挥发油的化学成分和抗菌活性研究[J].天然产物研究与开发,1999,1](6)：1.
[36]Niwa M, Iguchi M, Yamamua. The structure of C17-obtusilactone and two C21-obtusiliactone [J]. Tetrahedron Lett,1975:4395
[37]Katsura Seki, Takayuki Sasaki, Kazuo Haga, et al. Two methoxybutanolides from Lindera glauca [J]. Phytochemistry,1994,36(4):949-951
[38]Katura Seki, Takayuki Sasaki, Sutoshi wano, et al. Linderanolide and isolinderanolides, ten butanolides from Lindera glauca [J]. Phytochemistry, 1984,40(4):1175-1181.
[39]Jone anderson, Wenwen Ma, David LSmith, et al. Biologically active y-lactone and methylketoalkene from Lindera benzon [J]. J Nat Prod,1992, 55(1):71-83.
[40]张朝凤,孙启时,王峥涛,等.乌药叶化学成分研究[J].中国中药杂志,2001,26(11)：765.
[41]Kouno I, HiraiA, Fukusbige A, et al. New eudesmane sesquiterpenes from the root of Lindera strychnifolia [J] Nat Prod,2001,64(3):286.
[42]Zhang CF, Norio Nakamura, Sup inya Tewtrakul, et al. Sesquiterpenes and Alkaloids from Lindera chunii and their Inhibitory Activities against H IV-1 Integrase [J]. Chem, Pharm. Bull,2002,50(9):1195.
[43]Jian BL, YiD, WeiMl. A new sesquiterpene from the roots of Lindera Strychnifolia [J]. Chinese Chermical Letters,2002,13(10):965.
[44]Chou GX, Norio Nakamura, Ma CM, et al. Seven New Sesquiterpene Lactones from Lindera aggregata [J]. Journal of China Pharmaceutical University,200, 31(5):339.
[45]Isao Kouno, Asuka Hirai, Jiang ZH, et al. Bisequiterpenoid from the root of Lindera strychnifolia [J]. Phytochemistry,1997,46(7):1283.
[46]Hayashi Nanao, Komae Hisashi. Chemistry and distribution of sesquiterene. Furan in lauraceae [J]. Biochem Syst Ecol,1980,8(4):381-383.
[47]刘立鼎,陈京达,兰胜贵.山胡椒果实化学成分研究及应用实验[J].植物学报,1982,24(3)：252-258.
[48]Kazuhiko Ichino, Hitoshi Tanako, Kszuo Ito. A lignon from Lindera praecox [J]. Phytochemistry,1988,27(6):1096.
[49]Nobuhisa Ezaki, Masahide Kato, Nobuo Takizama, et al. Pharmacological studies on Lindera umbellata RumsⅣ[J]. Planta Medica,1985, (51):34-38.
[50]Yoshihiro Mimaki, Aiko Kameyama, Yutaka sashida, et al. A novel hexahydrodibenzofuran derivative with potent inhibitory activity on melanin biosynthesis of cultured B-16 melanoma cell from Lindera umbellate bark [J]. Chem Pharm Bull,1995,43(5):893-895.
[51]雷载权.中药学[M].上海：上海科学技术出版社,1995：164.
[52]张茂江.乌药的临床应用[J].四川中医,1994,12(5)：18.
[53]中国药材公司.中国中药资源志要[M].北京：科学出版社,1994：287.
[54]张树云.毛黑壳楠树皮中荷包牡丹碱的提取[J].中草药,1994.
[55]余德贵.山胡椒的药理作用[J].基层中药杂志,1996,10(4)：41.
[56]钱学射,肖正春.山胡椒的研究与利用.商业部南京野生植物综合利用研究所.
[57]张天明,胡珍姣,欧黎红.三种中草药抗病毒的实验研究[J].辽宁中医杂志,1994,21(11)：523-524.
[58]张小云,覃文庆,喻连香.山胡椒挥发油的提取及其抑菌活性研究[J].现代生物医学进展,2010,10(1)：133-136.
[59]Kang JJ, Cheng YW. Effects of boldine on mouse diaphragm and sarcoplasmic reticulum vesicles isolated from skeletal muscle [J]. Planta Med,1998,64: 18-21.
[60]Speisky H, Squella JA, Ntmez-Vergara LJ. Activity of boldine on rat ileum. Planta Med,1991,57:519-522.
[61]赵利琴.山胡椒属萜类及其生物活性研究进展.时珍国医国药,2006,17(2)： 171-174.
[62]桂新,王峥涛,徐珞珊,等.乌药化学成分及药理作用[J].中国野生植物资源,1998,18(3)：5.
[63]KobayashiW. miyase T, SanoM, Umehara K, et al. Prolyl endopep tidase inhibitors from the roots ofLindera strychnifolia F. Vill [J]. Biol Pharm Bull, 2002,25(8):1049.
[65]Li YM, Ohno, Minatoguchi S, Fukuda K, et al. Extracts from the roots of Lindera strychifolia induces apop tosis in lung cancer cells and prolongs survival of tumor-bearing mice [J]. Am J Cjin Med,2003,31(6):857.
[66]李智.乌药应用经验[J].江西中西药,1994,25(4)：63.
[67]彭墩.乌药治疗泌尿系统结石[J].甘肃中医,1994,7(5)：34.
[68]河南省卫生厅.河南省药品标准[S].郑州：河南科学技术出版社,1984：157.