红茴香、野八角的化学成分与抗HBV和抗口腔菌活性研究
其他题名CHEMICAL CONSTITUENTS AND ANTI-HBV, ANTI-ORAL MICROBIAL ACTIVITIES OF ILLICIUM HENRYI AND ILLICIUM SIMONSII
柳继锋
学位类型博士
导师陈纪军
2009-05-19
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业植物学
关键词红茴香 野八角 大青叶 化学成分 抗-hbv 活性 抗口腔有害菌活性
摘要本论文围绕抗乙型肝炎病毒 (hepatitis B virus, HBV) 与抗口腔有害菌等活性成分的发现, 选择八角科 (Illiciaceae) 红茴香 (Illicium henryi Diels.)、野八角 (Illicium simonsii Maxim.) 和十字花科 (Cruciferae) 大青叶(Isatis indigotica Fort.) 进行了较深入的化学成分分离与鉴定。从上述三种植物中分离鉴定了97个化合物,化合物类型涉及倍半萜、苯丙素、黄酮、生物碱、芳香酸等类型。其中新化合物14个,包括一个新颖的倍半萜内酯类化合物红茴香内酯A (henrylactone A) 和一个新颖的生物碱类化合物9, 13 - dihydroxylisopropylidenylisatisine A。 采用含有HBV基因组的质粒转染的肝癌细胞株Hep G 2.2.15 细胞测定化合物对乙肝病毒表面抗原 (HBsAg) 和e抗原 (HBeAg) 分泌的抑制作用进行抗乙肝病毒活性研究。首次发现了八角属中特有的seco-prezizaane类倍半萜内酯具有抗HBV活性,其中倍半萜内酯类化合物东亚八角素 (tashironin) 和 tashironin A 对 HBsAg和HBeAg 的分泌具有较好的抑制作用,IC50分别是0.48 mM、0.49 mM,选择指数 (selective index, SI) 分别为6.3,20.1;2.1,6.7。 抗口腔菌活性研究测定了化合物对7株受试菌株:粘性放线菌 (Actinomyces viscosus)、变形链球菌 (Streptocococcus mutans)、血链球菌 (Streptococcus sanguinis)、内氏放线菌 (Actinomyces naeslundii)、牙龈卟啉单胞菌 (Porphyromonas gingivalis)、具核梭杆菌 (Fusobacterium nucleatum)、嗜血放线伴生杆菌 (Actinobacillus actinomycetemcomitans) 的抑制作用。首次发现三苯基新木脂素类化合物具有抗口腔有害菌活性,野八角素A (simonin A)、红花八角醇 (dunnianol)、大花八角醇 (macranthol)、异红花八角醇 (isodunnianol) 对受试菌,特别是其中的革兰氏阳性菌的生长具有较强的抑制作用,MIC (minimal inhibitory concentration) 值在1.95-31.15 μg/mL之间。 论文的最后一章围绕研究内容对八角属中所报道的149个萜类化合物进行了综述,并根据化合物结构特点进行了分类。 第一章 红茴香的化学成分与抗HBV 活性研究 红茴香 (Illicium henryi Diels.) 为八角科 (Illiciaceae) 八角属 (Illicium) 植物,主要分布于我国云南、四川、贵州等地,民间根皮入药,具有散淤痛,祛风除湿的功效,其果实常被当作八角误食引起中毒,其化学成分主要包括倍半萜和黄酮等。前期的活性筛选发现红茴香茎和根的乙醇提取物具有抑制乙肝病毒表面抗原 (HBsAg) 和e抗原 (HBeAg) 分泌的活性,IC50分别是2.96 mg/mL、1.31 mg/mL,选择指数SI分别为2.2、1.4。为寻找活性成分,对红茴香的化学成分进行了研究,运用波谱学的方法鉴定了48个化合物,化合物类型主要为倍半萜内酯,苯丙素等,分别为:红茴香内酯A-E (henrylactone A-E, 1-5)、cycloparvifloralone (6)、东亚八角素 (tashironin, 7)、tashironin A (8)、 新莽草毒素 (neoanisatin, 9)、莽草毒素 (anisatin, 10)、莽草内酯B (anislactone B, 11)、7 - O - 乙酰基 - 莽草内酯B (7 - O - acetylanislactone B, 12)、merrillianolide (13)、cyclomerrillianolide (14), 伪大八角素 (pseudomajucin, 15)、dihydrodehydrodiconiferyl alcohol - 9 - O - β - D - (3'' - acetyl) - xylopyranoside (16)、(-) - dihydrodehydrodiconiferyl alcohol (17)、ficusal (18)、蛇菰脂醛素(balanophonin, 19)、dihydrodehydrodiconiferyl alcohol - 9 - O - α - L - rhamnopyranoside (20)、dihydrodehydrodiconiferyl alcohol 9 - O - β - xylopyranoside (21)、(2, 3 - trans) - 2, 3 - dihydro - 2 - [3' - methoxy - 4' - (1'', 3'' - dihydroxy - 2'' - propyloxy) phenyl] - 3 - hydroxymethyl - 7 - methoxy - 5 – benzofuran - propanol (22)、树脂醇 (sakuraresinol, 23)、aviculin (24)、rubriflosides A (25)、threo - 4, 9, 9' - trihydroxyl - 3, 3' - dimethoxy - 8 - O - 4' - neolignan - 7 - O - α - L - rhamnopyranoside (26)、7S, 8S - threo - 4, 9, 9' - trihydroxy - 3, 3' - dimethoxy - 8 - O - 4' - neolignan - 7 - O - β - D - glucopyranoside (27)、4 - O - (2′ - hydroxyl - 1′ - hydroxymethylethyl) - dihydroconiferyl alcohol 6′′ - p - hydroxylbenzoyl - glucoside (28)、4 - O - (2′ - hydroxy - 1′ - hydroxylmethylethyl) - dihydroconiferyl alcohol vanilloyl - glucoside (29)、(R) - 1 - O - (β - D - glucopyranosyl) - 2 - [2 - methoxy - 4 - (ω) - hydroxypropyl - phenoxyl] - propan - 3 - ol (30)、(S) - 1 - O - (β - D - glucopyranosyl) - 2 - [2 - methoxy - 4 - (ω) - hydroxypropyl - phenoxyl] - propan - 3 - ol (31)、(1S, 2R) - 1 - (4' - hydroxy - 3' - methoxypheny) - 2 - (4'' - hydroxy - 3'' - methoxyphenyl) - 1, 3 - propanediol (32)、dihydrodehydrodiconiferyl alcohol 9 - O - β - xylopyranoside (33)、1 - (3', 4' - dihydroxyphenyl) - 3 - (2'', 4'', 6'' - trihydroxyl) propan - 1, 2 - diol (34)、jasopyran (35)、松柏醛 (coniferaldehyde, 36)、芥子醛 (sinapaldehyde, 37)、反式 - 咖啡醛 (trans - caffeic aldehyde, 38)、山奈酚 (kaempferol, 39)、槲皮素 (quercetin, 40)、(2R, 3R) - 3, 5, 7, 3', 5' - 五羟基黄烷 ((2R, 3R) - 3, 5, 7, 3', 5' - pentahydroxyflavan, 41)、breynioside A (42)、1 - O - 3', 4', 5' - trimethoxyphenyl - β - D - glucopyranoside (43)、1 - O - 3', 4', - dimethoxyphenyl - β - D - glucopyranoside (44)、2, 6 - 二羟基 - 苯甲醛 (2, 6 - dihydroxyl - benzaldehyde, 45)、2 - 羟基 - 4 - 甲氧基 - 苯甲醛 (2 - hydroxyl - 4 - methoxy - benzaldehyde, 46)、 β - 谷甾醇 (β - sitosterol, 47)、胡萝卜苷 (daucosterol, 48)。其中化合物1-5、16、26为新化合物。 对所分离得到的部分化合物经抗HBV活性筛选发现,倍半萜内酯类化合物,特别是化合物东亚八角素 (tashironin, 7) 和tashironin A (8) 显示潜在的抗HBV活性,IC50分别是0.48 mM、0.49 mM,对乙肝病毒表面抗原 (HBsAg)和e抗原 (HBeAg) 选择指数SI分别为6.3,20.1和2.1,6.7。这也是首次发现八角属中所特有的seco-prezizaane类倍半萜内酯具有抗HBV活性,值得进一步研究。另外从中分离得到的一些木脂素类化合物也具有一定的抗HBV 活性。 第二章 野八角的化学成分与抗口腔菌活性成分研究 野八角 (Illicium simonsii Maxim.) 是八角科 (Illiciaceae) 八角属 (Illicium)植物,产于我国云南、四川、贵州及印度和缅甸等地,主要有挥发油、倍半萜内酯、黄酮等成分。前期的活性筛选发现,该植物的乙醇提取物对粘性放线菌 (Actinomyces viscosus) 具有较好的抑制作用 (MIC = 31.5 μg/mL)。通过进一步活性筛选发现石油醚萃取部分 (MIC = 19.5 μg/mL) 和氯仿萃取部分 (MIC = 19.5 μg/mL) 具有较好的抗菌活性,正丁醇部分和水层无抗菌活性 (MIC>250 μg/mL)。为了寻找活性成分,对野八角的茎和叶的化学成分进行了研究,从中分离鉴定了47个化合物,化合物类型涉及苯丙素、黄酮、倍半萜等类型,其结构鉴定为: 野八角素A (simonin A, 1)、1 - hydroxyl - 2 - O - β - D - 6′ - acetyl - glucopyranosyl - 4 - allylbenzene (2)、红花八角醇 (dunnianol, 3)、大花八角醇 (macranthol, 4)、异红花八角醇 (isodunnianol, 5)、厚朴酚 (manolol, 6)、dehydrodieugenol - B (7)、1 - hydroxy - 2 - O - β - D - glucopyranosyl - 4 - allylbenzene (8)、2 - (4′ - β - glucopyranosyloxy) - phenylethanol (9)、甲氧基丁子香酚 (4 - ally - 2, 6 – dimethoxyphenol, 10)、1 - (4' - hydroxyl - 3' - methoxypheny) - 2 - (4'' - hydroxyl - 3'' - methoxyphenyl) - 1, 3 - propanediol (11)、野八角内酯A (simonsilactone A, 12)、新大八角素 (neomajucin, 13)、莽草毒素 (anisatin, 14)、莽草内酯B (anislactone B, 15)、merrillianolide (16)、野八角素B (simonin B, 17)、oplodiol (18)、caryolane - 1, 9β - diol (19)、bullatantriol (20)、(-) - clovane - 2, 9 - diol (21), amorph - 4 - en - ol (22)、ent - oplopanone (23)、odoratisol C - 4 - O - β - D - glucopyranoside (24)、醉鱼草醇C (buddlenol C, 25)、醉鱼草醇D (buddlenol D, 26)、ficusesquilignan A (27)、leptolepisol A (28)、acernikol (29)、aviculin (30)、dihydrodehydrodiconiferyl alcohol 9 - O - β - D - glucopyranoside (31)、dihydrodehydrodiconiferyl alcohol 9 - O - β - D - xylopyranoside (32)、dihydrodehydrodiconiferyl alcohol 9 - O - α - L - rhamnopyranoside (33)、(-) - dihydrodehydrodiconiferyl alcohol (34)、山奈酚 (kaempferol, 35)、槲皮素 (quercetin, 36)、槲皮素 - 3 - O -  - L - 吡喃鼠李糖基 (1→6) - β - D - 吡喃葡萄糖苷 (quercetin 3 - O -  - L - rhamnopyranosyl - (1→6) - β - D - glucopyranoside, 37)、异鼠李素 - 3 - O - 芸香糖苷 (isorhamnetin 3 - O - robinoside, 38)、槲皮素- 3 - O -  - L - 吡喃鼠李糖苷 (quercetin - 3 - O -  - L - rhamnopyranoside, 39)、花旗松素 - 3 - O - β - D - 吡喃木糖苷 (taxifolin - 3 - O - β - D - xylopyranoside (40)、benzyl - 2 - O - β - D - glucopyranosyl - 2, 6 - dihydroxy - benzoate (41)、2, 4 - dihydroxy - 3, 6 - dimethyl - methyl benzoate (42)、biomdinin (43)、莽草酸 (shikimic acid, 44)、5 - 甲基 - 1, 3 - 苯二酚 (5 - methyl - 1, 3 - benzenediol, 45)、β - 谷甾醇 (β - sitosterol, 46)、胡萝卜苷 (daucosterol, 47)。其中化合物1、2、12、17、24为新化合物。 对所分离得到的含量较大的化合物进行了抗口腔有害菌的筛选,发现野八角素A (simonin A, 1)、红花八角醇 (dunnianol, 3)、大花八角醇 (macranthol, 4)、异红花八角醇 (isodunnianol, 5) 和厚朴酚 (manolol, 6) 对所筛选的口腔有害菌粘性放线菌 (Actinomyces viscosus)、变形链球菌 (Streptocococcus mutans)、血链球菌 (Streptococcus sanguinis)、内氏放线菌 (Actinomyces naeslundii)、牙龈卟啉单胞菌 (Porphyromonas gingivalis)、具核梭杆菌(Fusobacterium nucleatum)、嗜血放线伴生杆菌 (Actinobacillus actinomycetemcomitans),特别是对其中的革兰氏阳性菌具有比较好的抑制效果,其MIC值在1.95-31.15 μg/mL之间。这是首次发现三苯基新木脂素类化合物对革兰氏阳性菌的生长具有较好抑制作用。 第三章 大青叶中一个新奇生物碱的分离及鉴定 大青叶是十字花科 (Cruciferae) 菘蓝属 (Isatis) 植物菘蓝 (Isatis indigotica Fort.) 的干燥叶,其地下部分为板蓝根。主要分布在我国河北、江苏、浙江、安徽、河南等地,具有清热解毒,凉血利咽的功效,是我国常用的传统中药。在前期对大青叶乙醇提取物的化学成分研究的基础上,进一步对该植物化学成分进行研究,从中分离得到两个新的生物碱,其中9,13 - dihydroxylisopropylidenylisatisine A (1) 为一个新奇的生物碱,通过X-单晶衍射实验证实了该结构。抗病毒活性筛选显示该化合物具有中等的抗HIV活性。 第四章 八角属植物萜类化合物研究进展 本章总结了八角属植物中所报道的萜类化合物,特别是其所独有的seco-prezizaane型倍半萜内酯的研究进展。根据这些化合物的结构特点,对文献报道的149个化合物进行了归纳整理,并根据这些化学成分的结构特点进行了分类。
其他摘要In our continuing efforts to find anti - HBV (hepatitis B virus ) and anti - microbial agents from natural sources, the chemical constituents of Illicium henryi, Illicium simonsii and Isatis indigotica were investigated intensively to result in the isolation and identification of 97 compounds. The types of isolates involved in sesquiterpene, phenypropanoid, flavonoid, alkaloid and aromatic acid. Among them, 14 new compounds, including a novel sesquiterpene lactone, henrylactone A, and an unique alkaloid, 9,13 - dihydroxylisopropylidenylisatisine A, were elucidated based on spectroscopic methods, The isolates were evaluated for their anti-HBV activities in the HBV transfected Hep G 2.2.15 cell line in vitro and anti-microbial activites against Actinomyces viscosus, Streptocococcus mutans, Streptococcus sanguinis, Actinomyces naeslundii, Porphyromonas gingivalis, Fusobacterium nucleatum and Actinobacillus actinomycetemcomitans. The most active compound, tashironin A showed an IC50 value of 0.48 mM in inhibiting HBsAg secretion with a selectivity index (SI = 6.3) and an IC50 value of 0.15 mM (SI = 20.1) inhibiting HBeAg secretion of the Hep G2.2.15 cells. Compounds simonin A, dunnianol, macranthol, isodunnianol and manolol exhibited significant anti-microbial activity with MIC (minimal inhibitory concentration) from 1.95 to 31.25 μg/mL. It is the first time to find the seco-prezizaane type sesquiterpene lactones with anti-HBV activity and triphenyl-type neolignan compound with anti-microbial activity. Chapter 1 Active Anti-HBV Constituents from Illicium henryi Illicium henryi, belonging to the genus Illicium (Illiciaceae) is an evergreen shrub indigenous to the eastern Asia. Its bark and roots have been used as a folk medicinal herb for dispelling pathogenic wind and assuaging pain. In continuing efforts to discover anti-HBV agents from natural sources, the EtOH extract of stems and roots of I. henryi was found to show inhibitory potency to the secretion of HBV surface antigen (HBsAg) (IC50 = 2.96 mg/mL, SI = 2.2) and HBV e antigen (HBeAg) (IC50 = 1.31 mg/mL, SI = 1.4) in HBV-infected 2.2.15 cells. Chemical investigation on this plant resulted in the isolation of 48 compounds as follows, henrylactone A-E, (1-5), cycloparvifloralone (6), tashironin (7), tashironin A (8), neoanisatin (9), anisatin (10), anislactone B (11), 7 - O - acetylanislactone B (12), merrillianolide (13), cyclomerrillianolide (14), pseudomajucin (15), dihydrodehydrodiconiferyl alcohol 9 - O - β - D - (3'' - acetyl) - xylopyranoside (16), (-) - dihydrodehydrodiconiferyl alcohol (17), ficusal (18), balanophonin (19), dihydrodehydrodiconiferyl alcohol 9 - O - α - L - rhamnopyranoside (20), dihydrodehydrodiconiferyl alcohol 9 - O - β - xylopyranoside (21), (2, 3 - trans) - 2, 3 - dihydro - 2 - [3' - methoxy - 4' - (1'', 3'' - dihydroxy - 2'' - propyloxy) phenyl] - 3 - hydroxymethyl - 7 - methoxy - 5 - benzofuran - propanol (22), sakuraresinol (23), aviculin (24), rubriflosides A (25), threo - 4, 9, 9' - trihydroxyl - 3, 3' - dimethoxy - 8 - O - 4' - neolignan - 7 - O - α - L - rhamnopyranoside (26), 7S, 8S - threo - 4, 9, 9' - trihydroxy - 3, 3' - dimethoxy - 8 - O - 4' - neolignan - 7 - O - β - D - glucopyranoside (27), 4 - O - (2′ - hydroxyl - 1′ - hydroxymethylethyl) - dihy droconiferyl alcohol 6′′ - p - hydroxyl benzoyl - glucoside (28), 4 - O - (2′ - hydroxy - 1′ - hydroxylmethylethyl) - dihydroconiferyl alcohol vanilloyl - glucoside (29), (R) - 1 - O - (β - D - glucopyranosyl) - 2 - [2 - methoxy - 4 - (ω) - hydroxypropyl - phenoxyl] - propan - 3 - ol (30), (S) - 1 - O - (β - D - glucopyranosyl) - 2 - [2 - methoxy - 4 - (ω) - hydroxypropyl - phenoxyl] - propan - 3 - ol (31), (1S, 2R) - 1 - (4' - hydroxy - 3' - methoxypheny) - 2 - (4'' - hydroxy - 3'' - methoxyphenyl) - 1, 3 - propanediol (32), dihydrodehydrodiconiferyl alcohol 9 - O - β - xylopyranoside (33), 1 - (3', 4' - dihydroxyphenyl) - 3 - (2'', 4'', 6'' - trihydroxyl) propan - 1, 2 - diol (34), jasopyran (35), coniferaldehyde (36), sinapaldehyde (37), trans - caffeic aldehyde (38), kaempferol (39), quercetin (40), (2R, 3R) - 3, 5, 7, 3', 5' - pentahydroxyflavan (41), breynioside A (42), 1 - O - 3', 4', 5' - trimethoxyphenyl - β - D - glucopyranoside (43), 1 - O - 3', 4', - dimethoxyphenyl - β - D - glucopyranoside (44), 2, 6 - dihydroxyl - benzaldehyde (45), 2 - hydroxyl - 4 - methoxy - benzaldehyde (46), β - sitosterol (47), daucosterol (48). Among them, compounds 1-5, 16 and 26 were new ones. The isolates were evaluated for their anti-HBV activities in the HBV transfected Hep G 2.2.15 cell line in vitro. The most active compound, tashironin (7), exhibited an IC50 value of 0.48 mM (SI = 6.3) inhibiting on HBV surface antigen (HBsAg) secretion and an IC50 value of 0.15 mM (SI = 20.1) inhibiting on HBV e antigen (HBeAg) secretion using HBV transfected Hep G2.2.15 cell line. This is the first time to find the seco-prezizaane type sesquiterpene lactone with anti-HBV activity, which are worthy of further study. Chapter 2 Active Anti-oral Microbial Constituents from Illicium simonsii Illicium simonsii, belonging to the genus Illicium (Illiciaceae), mainly distributed in the southwestern part of China. In a study conducted recently by our group, crude extracts of the leaves and stems of I. simonsii were found to have anti-oral microbial activity. To identify the constituents responsible for activity, bioassay-guided fractionation of the ethanol extract led to the isolation of 47 compounds, of which 5 compounds showed remarkable anti-microbial activity. Based on spectral analyses (UV, IR, 1D, 2D NMR and MS) and comparison with reported literatures, the isolated compounds were elucidated as, simonin A (1), 1 - hydroxyl - 2 - O - β - D - 6′ - acetyl - glucopyranosyl - 4 - allylbenzene (2), dunnianol (3), macranthol (4), isodunnianol (5), manolol (6), dehydrodieugenol - B (7), 1 - hydroxy - 2 - O - β - D - glucopyranosyl - 4 - allylbenzene (8), 2 - (4′ - β - glucopyranosyloxy) - phenylethanol (9), 4 - ally - 2, 6 - dimethoxyphenol (10)、1 - (4' - hydroxyl - 3' - methoxypheny) - 2 - (4'' - hydroxyl - 3'' - methoxyphenyl) - 1, 3 - propanediol (11), simonsilactone A (12), neomajucin (13), anisatin (14), anislactone B (15), merrillianolide (16), simonin B (17), oplodiol (18), caryolane - 1, 9β - diol (19), bullatantriol (20), (-) - clovane - 2, 9 - diol (21), amorph - 4 - en - ol (22), ent - oplopanone (23), odoratisol C - 4 - O - β - D - glucopyranoside (24), buddlenol C (25), buddlenol D (26), ficusesquilignan A (27), leptolepisol A (28), acernikol (29), aviculin (30), dihydrodehydrodiconiferyl alcohol 9 - O - β - D - glucopyranoside (31), dihydrodehydrodiconiferyl alcohol 9 - O - β - D - xylopyranoside (32), dihydrodehydrodiconiferyl alcohol 9 - O - α - L - rhamnopyranoside (33), (-) - dihydrodehydrodiconiferyl alcohol (34), kaempferol, (35), quercetin (36), quercetin 3 - O - α- L - rhamnopyranosyl - (1→6) - β - D - glucopyranoside (37), isorhamnetin 3 - O - robinoside (38), quercetin - 3 - O - α- L - rhamnopyranoside (39), taxifolin - 3 - O - β - D - xylopyranoside (40), benzyl - 2 - O - β - D - glucopyranosyl - 2, 6 - dihydroxy - benzoate (41), 2, 4 - dihydroxy - 3, 6 - dimethyl - methyl benzoate (42), biomdinin (43), shikimic acid (44), 5 - methyl - 1, 3 - benzenediol (45), β - sitosterol (46), daucosterol (47). Among them, compounds 1, 2, 12, 17 and 24 were new ones. The isolates were tested for their anti-oral microbial activities. Compounds simonin A (1), dunnianol (3), macranthol (4), isodunnianol (5), manolol (6) isolated from active fraction exhibited significant inhibitory activities with MIC from 1.95 to 31.25 μg/mL against A. viscosus, S. mutans, S. sanguinis, A. naeslundii, P. gingivalis and A. actinomycetemcomitans. Chapter 3 Isolation and Identification of a Novel Alkaloid from Isatis indigotica Isatis indigotica Fort. (Cruciferae), is a biennial herbaceous plant species widely distributed and cultivated in China, had been used as a traditional Chinese medicine for the treatment of viral diseases including influenza, viral pneumonia, mumps, and hepatitis for hundreds of years in China. Further investigation on the aerial part of I. indigotica resulted in the isolation of a novel alkaloid 9,13- dihydroxylisopropylidenylisatisine A with moderate anti-HIV activity. Chapter 4 Review on Terpenoids from Illicium Species This review summarized the terpenes from the genus Illicium. In order to better understand the chemical structures, the terpenes were summarized and classified.
页数158
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/416
专题昆明植物所硕博研究生毕业学位论文
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柳继锋. 红茴香、野八角的化学成分与抗HBV和抗口腔菌活性研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2009.
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