穿心莲的化学成分及穿心莲新苷微生物转化研究
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摘要
常用中药穿心莲为爵床科穿心莲属植物穿心莲Andrographis paniculata(Burm．f．)Nees．的干燥地上部分。《中华人民共和国药典》(2000版)记载穿心莲：具有清热解毒，凉血消肿的功效。临床上主要用于风热感冒，咽喉肿痛，呼吸道感染，细菌性痢疾等疾病的治疗。
利用现代色谱手段从穿心莲的干燥地上部分分离得到50个化合物，通过化学和光谱学方法鉴定了其中45个化合物的结构，它们分别是：穿心莲新苷(neo-andrographolide)(1)，3，14-二去氧穿心莲内酯(3，14-di-deoxyandrographolide)(2)，穿心莲内酯(andrographolide)(3)，14-去氧-11，12-二去氢穿心莲内酯(14-deoxy-11，12-didehydroandrographolide)(4)，19-hydroxy-8(17)，13-ent-labdadien-15，16-olide(5)，14-去氧穿心莲内酯(14-deoxy-andrographolide)(6)，3-oxo-14-deoxyandrographolide(7)，3-oxo-14-deoxy-11，12-didehydroandrographolide(8)~*，异穿心莲内酯(isoandrographolide)(9)，双穿心莲内酯A(bisandrographolide A)(10)，双穿心莲内酯B(bisandrographolide B)(11)，双穿心莲内酯C(bisandrographolide C)(12)，3α，19-dihydroxy-15-methoxy-8(17)，11，13-ent-labdatrien-16，15-olide(13)~*，14-去氧-17β-羟基穿心莲内酯(14-deoxy-17β-hydroxyandrographolide)(14)，18-羟基-14-去氧穿心莲内酯(18-hydroxy-14-deoxyandrographolide)(15)~*，(12R)-羟基穿心莲内酯((12R)-12-hydroxyandrographolide)(16)~*，(12S)-羟基穿心莲内酯((12S)-12-hydroxyandrographolide)(17)~*，14-去氧穿心莲内酯苷(14-deoxyandrographiside)(18)，14-去氧-11，12-二去氢穿心莲内酯苷(14-deoxy-11，12-didehydroandrographolide)(19)，穿心莲内酯苷(andrographiside)(20)，(7R)-羟基-14-去氧穿心莲内酯((7R)-7-hydroxy-14-deoxyandrographolide)(21)~*，(7S)-羟基-14-去氧穿心莲内酯((7S)-7-hydroxy-14-deoxyandrographolide)(22)~*，14-去羟基穿心莲内酯(14-dehydroxy-andrographolide)(23)~*，β-D-glucopyranosyl-8(17)，13-ent-labdadien-16，15-olid-19-oate(24)~*，8(17)，13-ent-labdadiene-15，16，19-triol(25)~*，3α，15，19-trihydroxy-8(17)，13-ent-labdadien-16-oic acid(26)~*，双穿心莲内酯E(bisandrographolide E)(27)~*，双穿心莲内酯F(bisandrographolide F)(28)~*，3α，19-dihydroxy-14，15，16-trinor-ent-labd-8(17)，11-diene-13-oic acid(29)~*，3α，12，19-trihydroxy-13，14，15，16-tetranor-ent-labd-8(17)-ene (30)，7，8-二甲氧基-5-羟基黄酮(7，8-dimethoxy-5-hydroxyflavone)(31)，5-羟基-7，8-二甲氧基二氢黄酮(5-dihydroxy-7，8-dimethoxyflavanone)(32)，5-羟基-7，8，2′，5′-四甲氧基黄酮(5-hydroxy-7，8，2′，5′-tetramethoxyflavone)(33)，5-羟基-7，8，2′-三甲氧基黄酮(5-hydroxy-7，8，2′-trimethoxyflavone)(34)，5-羟基-7，8，2′，3′-四甲氧基黄酮(5-hydroxy-7，8，2′，3′-tetramethoxyflavone)(35)，5，4′-二羟基-7，8，2′，3′-四甲氧基黄酮(5，4′-dihydroxy-7，8，2′，3′-tetramethoxyflavone)(36)，5，2′-二羟基-7，8-二甲氧基二氢黄酮(5，2′-dihydroxy-7，8-dimethoxynavanone)(37)，5，7，8-三甲氧基二氢黄酮(5，7，8-trimethoxyflavanone)(38)，5，2′-二羟基-7，8-二甲氧基黄酮(5，2′-dihydroxy-7，8-dimethoxyflavone)(39)，5，4′-二羟基-7-甲氧基-8β-D-吡喃葡萄糖苷(5，4′-dihydroxy-7-methoxy-8β-D-glucopyranosyloxyflavone)(40)，andrographidine C(41)，7，8，2′，5′-四甲氧基-5β-D-吡喃葡萄糖苷(7，8，2′，5′-tetramethoxy-5β-Dglucopyranosyloxyflavone)(42)，andrographidine A(43)，5，7，4′-三羟基黄酮(5，7，4′-trihydroxyflavone)(44)，5，7，3′，4′-四羟基黄酮(5，7，3′，4′-tetrahydroxyflavone)(45)。这45个化合物中，30个为二萜内酯类及二萜内酯衍生物类化合物，15个为黄酮类化合物。其中化合物8，13，15，16，17，21，22，23，24，25，26，27，28，29，30，42共16个化合物为新化合物，化合物7，36为两个新的天然产物，化合物5，38，44，45为首次从该属植物中分离得到。
使用黑曲霉(Aspergillus niger，AS 3.739)对穿心莲中的主要二萜内酯类成分穿心莲新苷进行微生物转化研究，利用现代色谱手段从它的发酵液中共分离获得7种转化产物，通过化学和波谱学方法确定了其中5种转化产物的结构，分别是：8(17)，13-ent-labdadien-16，15-olid-19- oic acid(1)，3，14-二去氧穿心莲内酯(3，14-di-deoxyandrographolide)(2)，18-hydroxy-8(17)，13-ent-labdadien-16，15-olid-19-oic acid(3)，(3R)-hydroxy-8(17)，13-ent-labdadien-16，15-olid-19-oic acid (4)，(8S)，19-dihydroxy-ent-labd-13-en-16，15-olide(5)。这5个转化产物均为二萜内酯类化合物，其中转化产物3，4，5为新化合物。
目前，有关穿心莲中化学成分抗病毒活性的研究报道较少，且多与目前的临床适应症无关。本文通过对中药穿心莲化学成分以及穿心莲新苷微生物转化的研究，分离鉴定多种化学成分，为阐明穿心莲抗病毒药效成分，以及探讨抗病毒构效关系的研究奠定基础。
Chuanxinlian, the dried aerial parts of Andrographis paniculata (Burm.f.) Nees. is a Chinese herbal medicine used as an anti-inflammatory and antipyretic drug for treatment of fever, cold, laryngitis and diarrhea. And it was specified in the Pharmacopoeia of the P. R. China (2000) as an anti-virus and anti-bacterial remedy.The systematic investigation on chemical constituents led to the isolation of fifty compounds. On the basis of chemical evidences and spectral analysis, the structures of the 45 compounds were elucidated, and they are neoandrographolide (1), 3, 14-dideoxyandrographolide (2), andrographolide (3), 14-deoxy-11,12-didehydroandrographolide (4), 19-hydroxy-8(17), 13-ent-labdadien-15, 16-olide (5), 14-deoxy-andrographolide (6), 3-oxo-14-deoxyandrographolide (7), 3-oxo-14-deoxy-11, 12- didehydroandrographolide (8)*, isoandrographolide (9), bisandrographolide A (10), bisandrographolide B (11), bisandrographolide C (12), 3α, 19-dihydroxy-15-methoxy-8 (17), 11, 13-ent-labdatrien-16, 15-olide (13)*, (8S)-14-deoxy-17-hydroxyandrographolide (14), 18-hydroxy-14-deoxyandrographolide (15)*, (12R)-hydroxyandrographolide (16)*,(12S)-hydroxyandrographolide (17)*, 14-deoxyandrographiside (18), 14-deoxy-11, 12-didehydroandrographolide(19), andrographiside (20), (7R)-hydroxy-14-deoxyandrographolide (21)*, (7S)-hydroxy -14- deoxyandrographolide (22)*, 14-dehydroxy-andrographolide (23)*,β-D-glucopyranosyl- 8(17), 13-ent-labdadien-16, 15-olid-19-oate (24)*, 8(17), 13-ent-labdadiene-15, 16, 19-triol (25)*, 3α, 15, 19-trihydroxy-8(17), 13-ent-labdadien-16-oic acid (26)*, bisandrographolide E (27)*, bisandrographolide F (28)*, 3α, 19-dihydroxy-14, 15, 16-trinor-ent-labd-8(17), 11 -ene-13-oic acid (29)*, 3α, 12, 19-trihydroxy-13, 14, 15, 16-tetranor-ent-labd-8 (17)-ene (30)*, 7, 8-dimethoxy-5-hydroxyflavone (31), 5-dihydroxy-7, 8-dimethoxyflavanone (32), 5-hydroxy-7, 8, 2', 5'-tetramethoxyflavone (33), 5-hydroxy-7, 8, 2'-trimethoxyflavone (34), 5-hydroxy-7, 8, 2', 3'-tetramethoxyflavone (35), 5, 4'-dihydroxy-7, 8, 2', 3'-tetramethoxyflavone (36), 5, 2'-dihydroxy-7, 8-dimethoxyflavanone (37), 5, 7, 8-trimethoxyflavanone(38), 5, 2'-dihydroxy-7, 8-dimethoxyflavone (39), 5, 4'-dihydroxy-7-methoxy-8β-D-glucopyranosyloxyflavone(40), andrographidineC (41), 7, 8, 2', 5'-tetramethoxy-5β-D-glucopyranosyloxyflavone(42)~*, andrographidine A (43), 5, 7, 4'- trihydroxyflavone (44), 5, 7, 3', 4'-tetrahydroxyflavone (45), respectively. Among these 45 compounds, 30 are diterpenoid lactones and derivates of them, 15 are flavones. Among them, 8, 13, 15, 16, 17, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 and 42 are 16 new compounds, 7 and 36 are two new naturally occurring products isolated from Andrographis paniculata, 5, 38, 44 and 45 were isolated for the first time from Andrographis genus.
The microorganism Aspergillus niger, AS 3.739 was employed to bio-transform the substrate—neoandrographolide, seven products were isolated and purified from the fermented broth, and the structures of the five products were elucidated on the basis of chemical evidences and spectral analyses. The identified compounds are 8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (1), 3, 14-di-deoxyandrographolide (2), 18-hydroxy-8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (3)~*, (3R)-hydroxy-8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (4)~*, (8S), 19-dihydroxy-ent-labd-13-en-16, 15-olide (5)~*, respectively. Among these five products of diterpenoid lactones, 3, 4, and 5 are new compounds.
The above mentioned results would provide chemical substances for elucidating the antiviral constituents of Andrographis paniculata (Burm. f.) Nees., and further investigating antiviral structure-activity relationship.
利用现代色谱手段从穿心莲的干燥地上部分分离得到50个化合物，通过化学和光谱学方法鉴定了其中45个化合物的结构，它们分别是：穿心莲新苷(neo-andrographolide)(1)，3，14-二去氧穿心莲内酯(3，14-di-deoxyandrographolide)(2)，穿心莲内酯(andrographolide)(3)，14-去氧-11，12-二去氢穿心莲内酯(14-deoxy-11，12-didehydroandrographolide)(4)，19-hydroxy-8(17)，13-ent-labdadien-15，16-olide(5)，14-去氧穿心莲内酯(14-deoxy-andrographolide)(6)，3-oxo-14-deoxyandrographolide(7)，3-oxo-14-deoxy-11，12-didehydroandrographolide(8)~*，异穿心莲内酯(isoandrographolide)(9)，双穿心莲内酯A(bisandrographolide A)(10)，双穿心莲内酯B(bisandrographolide B)(11)，双穿心莲内酯C(bisandrographolide C)(12)，3α，19-dihydroxy-15-methoxy-8(17)，11，13-ent-labdatrien-16，15-olide(13)~*，14-去氧-17β-羟基穿心莲内酯(14-deoxy-17β-hydroxyandrographolide)(14)，18-羟基-14-去氧穿心莲内酯(18-hydroxy-14-deoxyandrographolide)(15)~*，(12R)-羟基穿心莲内酯((12R)-12-hydroxyandrographolide)(16)~*，(12S)-羟基穿心莲内酯((12S)-12-hydroxyandrographolide)(17)~*，14-去氧穿心莲内酯苷(14-deoxyandrographiside)(18)，14-去氧-11，12-二去氢穿心莲内酯苷(14-deoxy-11，12-didehydroandrographolide)(19)，穿心莲内酯苷(andrographiside)(20)，(7R)-羟基-14-去氧穿心莲内酯((7R)-7-hydroxy-14-deoxyandrographolide)(21)~*，(7S)-羟基-14-去氧穿心莲内酯((7S)-7-hydroxy-14-deoxyandrographolide)(22)~*，14-去羟基穿心莲内酯(14-dehydroxy-andrographolide)(23)~*，β-D-glucopyranosyl-8(17)，13-ent-labdadien-16，15-olid-19-oate(24)~*，8(17)，13-ent-labdadiene-15，16，19-triol(25)~*，3α，15，19-trihydroxy-8(17)，13-ent-labdadien-16-oic acid(26)~*，双穿心莲内酯E(bisandrographolide E)(27)~*，双穿心莲内酯F(bisandrographolide F)(28)~*，3α，19-dihydroxy-14，15，16-trinor-ent-labd-8(17)，11-diene-13-oic acid(29)~*，3α，12，19-trihydroxy-13，14，15，16-tetranor-ent-labd-8(17)-ene (30)，7，8-二甲氧基-5-羟基黄酮(7，8-dimethoxy-5-hydroxyflavone)(31)，5-羟基-7，8-二甲氧基二氢黄酮(5-dihydroxy-7，8-dimethoxyflavanone)(32)，5-羟基-7，8，2′，5′-四甲氧基黄酮(5-hydroxy-7，8，2′，5′-tetramethoxyflavone)(33)，5-羟基-7，8，2′-三甲氧基黄酮(5-hydroxy-7，8，2′-trimethoxyflavone)(34)，5-羟基-7，8，2′，3′-四甲氧基黄酮(5-hydroxy-7，8，2′，3′-tetramethoxyflavone)(35)，5，4′-二羟基-7，8，2′，3′-四甲氧基黄酮(5，4′-dihydroxy-7，8，2′，3′-tetramethoxyflavone)(36)，5，2′-二羟基-7，8-二甲氧基二氢黄酮(5，2′-dihydroxy-7，8-dimethoxynavanone)(37)，5，7，8-三甲氧基二氢黄酮(5，7，8-trimethoxyflavanone)(38)，5，2′-二羟基-7，8-二甲氧基黄酮(5，2′-dihydroxy-7，8-dimethoxyflavone)(39)，5，4′-二羟基-7-甲氧基-8β-D-吡喃葡萄糖苷(5，4′-dihydroxy-7-methoxy-8β-D-glucopyranosyloxyflavone)(40)，andrographidine C(41)，7，8，2′，5′-四甲氧基-5β-D-吡喃葡萄糖苷(7，8，2′，5′-tetramethoxy-5β-Dglucopyranosyloxyflavone)(42)，andrographidine A(43)，5，7，4′-三羟基黄酮(5，7，4′-trihydroxyflavone)(44)，5，7，3′，4′-四羟基黄酮(5，7，3′，4′-tetrahydroxyflavone)(45)。这45个化合物中，30个为二萜内酯类及二萜内酯衍生物类化合物，15个为黄酮类化合物。其中化合物8，13，15，16，17，21，22，23，24，25，26，27，28，29，30，42共16个化合物为新化合物，化合物7，36为两个新的天然产物，化合物5，38，44，45为首次从该属植物中分离得到。
使用黑曲霉(Aspergillus niger，AS 3.739)对穿心莲中的主要二萜内酯类成分穿心莲新苷进行微生物转化研究，利用现代色谱手段从它的发酵液中共分离获得7种转化产物，通过化学和波谱学方法确定了其中5种转化产物的结构，分别是：8(17)，13-ent-labdadien-16，15-olid-19- oic acid(1)，3，14-二去氧穿心莲内酯(3，14-di-deoxyandrographolide)(2)，18-hydroxy-8(17)，13-ent-labdadien-16，15-olid-19-oic acid(3)，(3R)-hydroxy-8(17)，13-ent-labdadien-16，15-olid-19-oic acid (4)，(8S)，19-dihydroxy-ent-labd-13-en-16，15-olide(5)。这5个转化产物均为二萜内酯类化合物，其中转化产物3，4，5为新化合物。
目前，有关穿心莲中化学成分抗病毒活性的研究报道较少，且多与目前的临床适应症无关。本文通过对中药穿心莲化学成分以及穿心莲新苷微生物转化的研究，分离鉴定多种化学成分，为阐明穿心莲抗病毒药效成分，以及探讨抗病毒构效关系的研究奠定基础。
Chuanxinlian, the dried aerial parts of Andrographis paniculata (Burm.f.) Nees. is a Chinese herbal medicine used as an anti-inflammatory and antipyretic drug for treatment of fever, cold, laryngitis and diarrhea. And it was specified in the Pharmacopoeia of the P. R. China (2000) as an anti-virus and anti-bacterial remedy.The systematic investigation on chemical constituents led to the isolation of fifty compounds. On the basis of chemical evidences and spectral analysis, the structures of the 45 compounds were elucidated, and they are neoandrographolide (1), 3, 14-dideoxyandrographolide (2), andrographolide (3), 14-deoxy-11,12-didehydroandrographolide (4), 19-hydroxy-8(17), 13-ent-labdadien-15, 16-olide (5), 14-deoxy-andrographolide (6), 3-oxo-14-deoxyandrographolide (7), 3-oxo-14-deoxy-11, 12- didehydroandrographolide (8)*, isoandrographolide (9), bisandrographolide A (10), bisandrographolide B (11), bisandrographolide C (12), 3α, 19-dihydroxy-15-methoxy-8 (17), 11, 13-ent-labdatrien-16, 15-olide (13)*, (8S)-14-deoxy-17-hydroxyandrographolide (14), 18-hydroxy-14-deoxyandrographolide (15)*, (12R)-hydroxyandrographolide (16)*,(12S)-hydroxyandrographolide (17)*, 14-deoxyandrographiside (18), 14-deoxy-11, 12-didehydroandrographolide(19), andrographiside (20), (7R)-hydroxy-14-deoxyandrographolide (21)*, (7S)-hydroxy -14- deoxyandrographolide (22)*, 14-dehydroxy-andrographolide (23)*,β-D-glucopyranosyl- 8(17), 13-ent-labdadien-16, 15-olid-19-oate (24)*, 8(17), 13-ent-labdadiene-15, 16, 19-triol (25)*, 3α, 15, 19-trihydroxy-8(17), 13-ent-labdadien-16-oic acid (26)*, bisandrographolide E (27)*, bisandrographolide F (28)*, 3α, 19-dihydroxy-14, 15, 16-trinor-ent-labd-8(17), 11 -ene-13-oic acid (29)*, 3α, 12, 19-trihydroxy-13, 14, 15, 16-tetranor-ent-labd-8 (17)-ene (30)*, 7, 8-dimethoxy-5-hydroxyflavone (31), 5-dihydroxy-7, 8-dimethoxyflavanone (32), 5-hydroxy-7, 8, 2', 5'-tetramethoxyflavone (33), 5-hydroxy-7, 8, 2'-trimethoxyflavone (34), 5-hydroxy-7, 8, 2', 3'-tetramethoxyflavone (35), 5, 4'-dihydroxy-7, 8, 2', 3'-tetramethoxyflavone (36), 5, 2'-dihydroxy-7, 8-dimethoxyflavanone (37), 5, 7, 8-trimethoxyflavanone(38), 5, 2'-dihydroxy-7, 8-dimethoxyflavone (39), 5, 4'-dihydroxy-7-methoxy-8β-D-glucopyranosyloxyflavone(40), andrographidineC (41), 7, 8, 2', 5'-tetramethoxy-5β-D-glucopyranosyloxyflavone(42)~*, andrographidine A (43), 5, 7, 4'- trihydroxyflavone (44), 5, 7, 3', 4'-tetrahydroxyflavone (45), respectively. Among these 45 compounds, 30 are diterpenoid lactones and derivates of them, 15 are flavones. Among them, 8, 13, 15, 16, 17, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 and 42 are 16 new compounds, 7 and 36 are two new naturally occurring products isolated from Andrographis paniculata, 5, 38, 44 and 45 were isolated for the first time from Andrographis genus.
The microorganism Aspergillus niger, AS 3.739 was employed to bio-transform the substrate—neoandrographolide, seven products were isolated and purified from the fermented broth, and the structures of the five products were elucidated on the basis of chemical evidences and spectral analyses. The identified compounds are 8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (1), 3, 14-di-deoxyandrographolide (2), 18-hydroxy-8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (3)~*, (3R)-hydroxy-8(17), 13-ent-labdadien-16, 15-olid-19-oic acid (4)~*, (8S), 19-dihydroxy-ent-labd-13-en-16, 15-olide (5)~*, respectively. Among these five products of diterpenoid lactones, 3, 4, and 5 are new compounds.
The above mentioned results would provide chemical substances for elucidating the antiviral constituents of Andrographis paniculata (Burm. f.) Nees., and further investigating antiviral structure-activity relationship.
引文
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12. Rao, Y. K., Vimalamma G., Rao, C. V., et al., Flavonoids and andrographolides from Andrographis paniculata, Phytochemistry, 2004, 65: 2317-2321
13. Jayaprakasam, B., Damu, A. G., Gunasekar D., et al., Dihydroechiodinin, a flavanone from Andrographis echioides, Phytochemistry, 1999, 52: 935-937
14. Muntha K. Reddy, Mopuru V. B., Duvvuru Gunasekar, et al., A flavone and an unusual 23-carbon terpenoid from Andrographis paniculata. Phytochemistry, 2003, 64: 1271-1275
15. Zhang, Y.Y., Guo, Y.Z., Onda, M., et al. Four flavonoids from Scutellaria baicalensis. Phytochemistry, 1989, 35:511-514
16．广州市药品检验所中草药科．穿心莲抗菌解热的药理实验．中草药研究，1974，3：46-48
17．陈国祥，丁伯平，陈斌，等．穿心莲胶囊的抗炎作用研究．现代中西医结合杂志，2001，10：1004-1005
18. Shen Y. C, Chen C. F., Chiou W. F. Suppression of rat neutrophil reactive oxygen species production and adhension dy the diterpenoid lactone andrographolide. Planta Medica, 2000, 66:314-317
19. Feinstein M. B., Egan J. J., Shaafi R. Ⅰ., et al., The cytoplastic concentration of free calcium in platelet is controlled by stimulation of cyclic AMP production (PGD_2, PGE_1, Forskolin), Biochem. Biophys. Res. Com., 1983, 113:598-605
20．熊一力，赵华月．穿心莲成分API_(0.134)对猪主动脉平滑肌细胞增殖的抑制作用．中华心血管杂志，1995，23：214-216
21．吴基良，刘敏，刘淑珍，等．穿心莲提取物的抗心肌缺血药理实验．中药药理与临床，1996．5：17
22．郭志凌，赵华月，苏厚芬，等．API_(0.134)对氧自由基和钙超负荷的作用．同济医科大学学报，1997，26：109-111，119
23．郭志凌，赵华月，郑信华．穿心莲提取液对缺血．在灌注心肌细胞内心，Na~+，Ca~(2+)、Mg~(2+)的作用．同济医科大学学报，1994，23：205-207
24．李树生，赵华月，郭志凌．API_(0.134)对凝血酶作用下血小板环核苷酸和胞浆钙离子浓度的影响．同济医科大学学报，1999，28：141-142，146
25．刘超，王勇民，马世玉，等．穿心莲注射液对麻醉大鼠血压的影响．咸宁医学院学报，2000．14：244-245
26．李立中，吴基良，郭贤成．穿心莲注射液对麻醉狗的降压作用．中医药研究，1997，13，46-47
27．赵华月，等．一种新的穿心莲成分的药理研究．中国循环杂志，1991，6：407-409
28．孙备．14-脱氧穿心莲内酯和14-脱氧-11，12-二去氢穿心莲内酯对培养的人内皮细胞NO生成的影响．中医中药分册，2000，22：100-101
29．王宏伟，赵华月，向世勤．API_(0.134)对LDL诱导单核细胞表达PDGF-B，bFGF及平滑肌增殖的抑制作用．中华心血管病杂志，1995，23：214-216
30. Lerman A., Burnett J. C. Intect and altered endothelium in regulation of vasomotion. Ciuculation, 1992, 86: Ⅲ-12-19
31. Trvedi, Z. P., Rawal U.M., Hepatoprotective and antioxidant property of Andrographis paniculata (Nees) in BHC induced liver damage in mice. Indian J. Exp. Biol., 2001, 39:41-46
32. Shukla B, Visen P. K. S., Patnaik G. K., et al., Choleretic effect of andrographoloid in rats and pigs, Planta Medica, 1992, 58:146-151
33．郭志凌，赵华月，郑信华，等．穿心莲成分API)(0.134)的抗HIV活性研究．中国中西医结合杂志，1997，17：547-549
34. Ajoy Basak, Sam Cooper, Andree G. Roberge, et al. Inhibition of proprotein convertases-1, -7 and furin by diterpenes ofAndrographis paniculata and their succinoyl esters. J. Biochem, 1999, 338:107-113
35. Puri A., Saxena R., Saxena R. P., et al. Immunostimulant agents from Andrographis paniculata. J. Nat. Prod., 1993, 56, 995-999
36．陈爱葵，黄清松，梁光发，等．穿心莲对小鼠E玫瑰花环形成率影响的研究．中国中医药信息杂志，1999，6：21
37．陈爱葵，黄清松，梁光发，等．穿心莲对小鼠腹腔巨噬细胞功能影响的研究．中国中医药信息杂志，1998，5：23-24
38. Akbarsha M. A., et al. Aspects of the male reproductive toxicity/male antifertility property of andrographolide in albino rats: effect on the tesis and the cauda epididymidal spermatozoa. Phytother. Res., 2000, 14:432-439
39. George, M., Pandalai, K.M. Investigations on plant antibiotics, Part Ⅳ. Further search for antibiotics substances in Indian medicinal plants. Indian J. Med. Res., 1949, 37: 169-181
40. Batkhuu J., Hattori K., Takano F., et al. Suppression of NO production in activated Macrophages in vitro and exvivo by neoandrographolide isolated from Andrographis paniculata. Biol. Pharm. BulL, 2002, 25: 1169-1174
41. Chiou W. F., Lin J. J., Chen C. F. Andrographolide suppress the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. British J. Pharm., 1998, 125:327-334
42．邓文龙，聂仁吉，刘家玉．四种穿心莲内酯的药理作用比较．药学通报，1982，17： 195-198
43．王玉生，等．中药药理与应用(第二版)．北京：人民卫生出版社，1998，866
44．褚志义主编．生物合成药物学．上海医科大学出版社，1991，188-193
45. Jones Sir E. R. H, Meakins G. D., John O. M. et al. Microbiological hydroxylation Part ⅩⅫ. Hydroxylation of 3, 20-7, 20-, and 11, 20-dioxygenated 5α- pregnanes. J. Chem. Sor. Parkin, 1976, 1842-1847
46. Hideaki Yamada, et al. Microbial and enzymatic processes for the production of biologically and chemically useful compounds. Angew Chem. Ipt. Ed. Engl., 1988, 27: 622-643
47. Abourashed E. A., Clark A. M., Hufford C. D. et al. Microbial model s of mammalian metabolism of xenobiotics (An updated review). Curt Med. Chem., 1999, 6:359-374
48. Zhang D., Yang Y., Leakey J. E. et al. Phase Ⅰ and phase Ⅱ enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbial Lett., 1996, 138:221-226
49．刘磊，孙璐，黄海华，等．奈普生的微生物转化．沈阳药科大学学报，2002，19：369-372
50. Moody J. D., Freeman J. P., Cemiglia C. E. Biotransformation of doxepin by Cunninghamella elegans. Drug Metab. Dispos., 1999, 27:1157-1164
51. Moody J. D., Zhang D., Heinze T. M. et al. Transformation of amoxapine by C. elegans. Appl. Environ. Microbiol., 2000, 66:3646-3649
52．黄海华，崔洪霞，钟大放，等．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
53. Rao G. P., Davis P. J. et al. Microbial models of mammalian metabolism biotransformations of HP 749 (Besipirdine) Using Cunninghamella elegans. Drug Metab. Dispos., 1997, 25:709-715
54. Zhang D., Freeman J. P., Sutherland J. B. et al. Biotransformation of chlorpromazine methdilazine by C. elegans. Appl. Environ. Microbiol., 1996, 62:793-803
55. Kieslich K. Biotransformation of industrial use. Acta Biotechnol., 1991, 6:559-570
56. Laszlo Poppe, et al. Selective Biocatalysis. VCH, Weinheim. New York, Cambridge, Basel. 1992:15-66
57．中国医学科学院药用植物资源开发研究所，中国医学科学院药用研究所等编．中药志Ⅳ 北京：科学技术出版社．1982：556-562
58. Haynes, L.J., In Peach, K., Tracey, MV. (Eds), Modem Methods in Plant Analysis, Vol. Ⅱ. Springer-Verlag, Berlin. 1955:583
59. Hsieh Y. L., Fang J. M., Cheng Y. S., Terpenoids and flavonoids from Pseudotsuga wilsoniana. Phytochemistry, 1998, 47:845-850
60. Waridel R, Wolfender J. L., Lachavanne J. B., et al. ent-Labdane glycosides from the aquatic Potamogeton lucens and analytical evaluation of the lipophilic extract constituents of various Potamogeton species. Phytochemistry, 2004, 65:945-954
61. Byung Hoon Han, Hyun Ok Yang, Young-Hwa Kang, et al. In vitro platelet- activating factor receptor binding inhibitory activity of pinusolide derivatives: a structure-activity study. J. Meal Chem., 1998, 41:2626-2630
62. S. Fukuzawa, S. Matsunaga, N. Fusetani, Ten more ritterazines, cytotoxic steroidal alkaloids from the Tunicate Ritterella tokioka. Tetrahedron, 1995, 51 : 6707-6716
63. Aranda G., Azerad R., Maurs M., et al. Microbial hydroxylation/functionalization of terpenoid synthons derived from communic acid. Phytochemistry, 2000, 54:23-27
64．姚新生主编，天然药物化学(第二版)．北京：人民卫生出版社．1999：394-395
65. Zdero C., Bohlmann F., King R. M. Guaianolides and labdanes from Brickellia species. Phytochemistry, 1991, 30:1591-1595
66. Misbah A. F. B., Rajesh K. G., Sanjay K. S., et al. A novel diterpenoid lactone-based scaffold for the generation of combinatorial libraries. Tetrahedron Letters, 2001, 42: 7119-7121
67. Shen Y. H., Li R. T., Xiao W. L., et al. ent-Labdane diterpenes from Andrographis paniculata. J. Nat. Prod, 2006, 69:319-322
68. Gupta, K.K., Taneja, S.C., Dhar, K.L., et al. Flavonoids of Andrographis paniculata. Phytochemistry, 1983, 22:314-315
69. Vijaya, M., Hari, P., Venkata, C., et al. New 2'-oxygenated flavonoids from Andrographis paniculata. J. Nat. Prod., 2003, 66:295-297
70. Darnu A. G., Jayaprakasam B., Rao K. V., et al. A flavone glycoside from Andrographis alata. Phytochemistry, 1998, 49:1811-1813
71. Jayaprakanasam, B., Gunasekar, D., Rao,K.V., et al. Androechin, a new chalcone glucoseide from Andrographis echioides. J Asian Nat Prod Res, 2001, 3:43-48
72. Saxena, Sudhanshu, Jain, D.C. Phytochemicals from Andrographis paniculata. Indian J. Chem. Section B, 2003, 42(B): 3159-3163
73．于德泉，杨峻山．分析化学手册(第二版)第七分册．北京：化学工业出版社，1999．817
74. Waridel P., Wolfender J. L., Lachavanne J. B., et al. ent-Labdane diterpenes from the aquatic plant Potamogeton pectinatus. Phytochemistry, 2003, 64:1309-1317
2．江苏新一学院编．《中药大辞典》(下册)，第一版，上海：上海科学技术出版社，1986：3551
3. Kleipool, R. J. C., Constituents of Andrographis paniculata Nees., Nature, 1952, 169: 33-34
4. Cava M. P., Chan W. R., Haynes L. J., et al., The structure of andrographolide, Tetrahedron, 1962, 18: 397-403
5. Fujita, T, Fujitani, R., Takeda, Y., et al., On the diterpenoids of Andrographispaniculata: X-ray crystallographic analysis of andrographolide and structure determination of new minor diterpenoids. Chem. Pharm. Bull., 1984, 32: 2117-2125
6. Matsuda. T, Kuroyanagi. M., Sugiyama. S., et al., Cell differentiation-inducing diterpenes from Andrographis paniculata Nees. Chem. Pharm. Bull., 1994, 42: 1216-1225
7. Chan, W. R., Taylor, D. R., Willis C. R., et al., The structure and stereochemistry of neoandrographolide, a diterpene glycoside from Andrographis paniculata Nees. Tetrahedron, 1971, 27: 5081-5091
8. Balmain, A., Connolly, J. D., Minor diterpenoid constituents of Andrographis paniculata Nees. J. Chem. Soc. Perkin Trans., Ⅰ 1973: 1247-1251
9. Chen, W. M., Liang X. T., Deoandrographolide-19β-D-Glucoside from the leaves of Andrographis paniculata, Planta Medica, 1982, 45: 245-246
10．胡昌奇，穿心莲中新的二萜内酯类成分研究．中草药，1981，12(12)，531-533
11. Kuroyanagi, M., Sato, M., Ueno, A., et al., Flavonoids from Andrographis paniculata, Chem Pharm Bull, 1987, 35: 4429-4435
12. Rao, Y. K., Vimalamma G., Rao, C. V., et al., Flavonoids and andrographolides from Andrographis paniculata, Phytochemistry, 2004, 65: 2317-2321
13. Jayaprakasam, B., Damu, A. G., Gunasekar D., et al., Dihydroechiodinin, a flavanone from Andrographis echioides, Phytochemistry, 1999, 52: 935-937
14. Muntha K. Reddy, Mopuru V. B., Duvvuru Gunasekar, et al., A flavone and an unusual 23-carbon terpenoid from Andrographis paniculata. Phytochemistry, 2003, 64: 1271-1275
15. Zhang, Y.Y., Guo, Y.Z., Onda, M., et al. Four flavonoids from Scutellaria baicalensis. Phytochemistry, 1989, 35:511-514
16．广州市药品检验所中草药科．穿心莲抗菌解热的药理实验．中草药研究，1974，3：46-48
17．陈国祥，丁伯平，陈斌，等．穿心莲胶囊的抗炎作用研究．现代中西医结合杂志，2001，10：1004-1005
18. Shen Y. C, Chen C. F., Chiou W. F. Suppression of rat neutrophil reactive oxygen species production and adhension dy the diterpenoid lactone andrographolide. Planta Medica, 2000, 66:314-317
19. Feinstein M. B., Egan J. J., Shaafi R. Ⅰ., et al., The cytoplastic concentration of free calcium in platelet is controlled by stimulation of cyclic AMP production (PGD_2, PGE_1, Forskolin), Biochem. Biophys. Res. Com., 1983, 113:598-605
20．熊一力，赵华月．穿心莲成分API_(0.134)对猪主动脉平滑肌细胞增殖的抑制作用．中华心血管杂志，1995，23：214-216
21．吴基良，刘敏，刘淑珍，等．穿心莲提取物的抗心肌缺血药理实验．中药药理与临床，1996．5：17
22．郭志凌，赵华月，苏厚芬，等．API_(0.134)对氧自由基和钙超负荷的作用．同济医科大学学报，1997，26：109-111，119
23．郭志凌，赵华月，郑信华．穿心莲提取液对缺血．在灌注心肌细胞内心，Na~+，Ca~(2+)、Mg~(2+)的作用．同济医科大学学报，1994，23：205-207
24．李树生，赵华月，郭志凌．API_(0.134)对凝血酶作用下血小板环核苷酸和胞浆钙离子浓度的影响．同济医科大学学报，1999，28：141-142，146
25．刘超，王勇民，马世玉，等．穿心莲注射液对麻醉大鼠血压的影响．咸宁医学院学报，2000．14：244-245
26．李立中，吴基良，郭贤成．穿心莲注射液对麻醉狗的降压作用．中医药研究，1997，13，46-47
27．赵华月，等．一种新的穿心莲成分的药理研究．中国循环杂志，1991，6：407-409
28．孙备．14-脱氧穿心莲内酯和14-脱氧-11，12-二去氢穿心莲内酯对培养的人内皮细胞NO生成的影响．中医中药分册，2000，22：100-101
29．王宏伟，赵华月，向世勤．API_(0.134)对LDL诱导单核细胞表达PDGF-B，bFGF及平滑肌增殖的抑制作用．中华心血管病杂志，1995，23：214-216
30. Lerman A., Burnett J. C. Intect and altered endothelium in regulation of vasomotion. Ciuculation, 1992, 86: Ⅲ-12-19
31. Trvedi, Z. P., Rawal U.M., Hepatoprotective and antioxidant property of Andrographis paniculata (Nees) in BHC induced liver damage in mice. Indian J. Exp. Biol., 2001, 39:41-46
32. Shukla B, Visen P. K. S., Patnaik G. K., et al., Choleretic effect of andrographoloid in rats and pigs, Planta Medica, 1992, 58:146-151
33．郭志凌，赵华月，郑信华，等．穿心莲成分API)(0.134)的抗HIV活性研究．中国中西医结合杂志，1997，17：547-549
34. Ajoy Basak, Sam Cooper, Andree G. Roberge, et al. Inhibition of proprotein convertases-1, -7 and furin by diterpenes ofAndrographis paniculata and their succinoyl esters. J. Biochem, 1999, 338:107-113
35. Puri A., Saxena R., Saxena R. P., et al. Immunostimulant agents from Andrographis paniculata. J. Nat. Prod., 1993, 56, 995-999
36．陈爱葵，黄清松，梁光发，等．穿心莲对小鼠E玫瑰花环形成率影响的研究．中国中医药信息杂志，1999，6：21
37．陈爱葵，黄清松，梁光发，等．穿心莲对小鼠腹腔巨噬细胞功能影响的研究．中国中医药信息杂志，1998，5：23-24
38. Akbarsha M. A., et al. Aspects of the male reproductive toxicity/male antifertility property of andrographolide in albino rats: effect on the tesis and the cauda epididymidal spermatozoa. Phytother. Res., 2000, 14:432-439
39. George, M., Pandalai, K.M. Investigations on plant antibiotics, Part Ⅳ. Further search for antibiotics substances in Indian medicinal plants. Indian J. Med. Res., 1949, 37: 169-181
40. Batkhuu J., Hattori K., Takano F., et al. Suppression of NO production in activated Macrophages in vitro and exvivo by neoandrographolide isolated from Andrographis paniculata. Biol. Pharm. BulL, 2002, 25: 1169-1174
41. Chiou W. F., Lin J. J., Chen C. F. Andrographolide suppress the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide. British J. Pharm., 1998, 125:327-334
42．邓文龙，聂仁吉，刘家玉．四种穿心莲内酯的药理作用比较．药学通报，1982，17： 195-198
43．王玉生，等．中药药理与应用(第二版)．北京：人民卫生出版社，1998，866
44．褚志义主编．生物合成药物学．上海医科大学出版社，1991，188-193
45. Jones Sir E. R. H, Meakins G. D., John O. M. et al. Microbiological hydroxylation Part ⅩⅫ. Hydroxylation of 3, 20-7, 20-, and 11, 20-dioxygenated 5α- pregnanes. J. Chem. Sor. Parkin, 1976, 1842-1847
46. Hideaki Yamada, et al. Microbial and enzymatic processes for the production of biologically and chemically useful compounds. Angew Chem. Ipt. Ed. Engl., 1988, 27: 622-643
47. Abourashed E. A., Clark A. M., Hufford C. D. et al. Microbial model s of mammalian metabolism of xenobiotics (An updated review). Curt Med. Chem., 1999, 6:359-374
48. Zhang D., Yang Y., Leakey J. E. et al. Phase Ⅰ and phase Ⅱ enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. FEMS Microbial Lett., 1996, 138:221-226
49．刘磊，孙璐，黄海华，等．奈普生的微生物转化．沈阳药科大学学报，2002，19：369-372
50. Moody J. D., Freeman J. P., Cemiglia C. E. Biotransformation of doxepin by Cunninghamella elegans. Drug Metab. Dispos., 1999, 27:1157-1164
51. Moody J. D., Zhang D., Heinze T. M. et al. Transformation of amoxapine by C. elegans. Appl. Environ. Microbiol., 2000, 66:3646-3649
52．黄海华，崔洪霞，钟大放，等．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
53. Rao G. P., Davis P. J. et al. Microbial models of mammalian metabolism biotransformations of HP 749 (Besipirdine) Using Cunninghamella elegans. Drug Metab. Dispos., 1997, 25:709-715
54. Zhang D., Freeman J. P., Sutherland J. B. et al. Biotransformation of chlorpromazine methdilazine by C. elegans. Appl. Environ. Microbiol., 1996, 62:793-803
55. Kieslich K. Biotransformation of industrial use. Acta Biotechnol., 1991, 6:559-570
56. Laszlo Poppe, et al. Selective Biocatalysis. VCH, Weinheim. New York, Cambridge, Basel. 1992:15-66
57．中国医学科学院药用植物资源开发研究所，中国医学科学院药用研究所等编．中药志Ⅳ 北京：科学技术出版社．1982：556-562
58. Haynes, L.J., In Peach, K., Tracey, MV. (Eds), Modem Methods in Plant Analysis, Vol. Ⅱ. Springer-Verlag, Berlin. 1955:583
59. Hsieh Y. L., Fang J. M., Cheng Y. S., Terpenoids and flavonoids from Pseudotsuga wilsoniana. Phytochemistry, 1998, 47:845-850
60. Waridel R, Wolfender J. L., Lachavanne J. B., et al. ent-Labdane glycosides from the aquatic Potamogeton lucens and analytical evaluation of the lipophilic extract constituents of various Potamogeton species. Phytochemistry, 2004, 65:945-954
61. Byung Hoon Han, Hyun Ok Yang, Young-Hwa Kang, et al. In vitro platelet- activating factor receptor binding inhibitory activity of pinusolide derivatives: a structure-activity study. J. Meal Chem., 1998, 41:2626-2630
62. S. Fukuzawa, S. Matsunaga, N. Fusetani, Ten more ritterazines, cytotoxic steroidal alkaloids from the Tunicate Ritterella tokioka. Tetrahedron, 1995, 51 : 6707-6716
63. Aranda G., Azerad R., Maurs M., et al. Microbial hydroxylation/functionalization of terpenoid synthons derived from communic acid. Phytochemistry, 2000, 54:23-27
64．姚新生主编，天然药物化学(第二版)．北京：人民卫生出版社．1999：394-395
65. Zdero C., Bohlmann F., King R. M. Guaianolides and labdanes from Brickellia species. Phytochemistry, 1991, 30:1591-1595
66. Misbah A. F. B., Rajesh K. G., Sanjay K. S., et al. A novel diterpenoid lactone-based scaffold for the generation of combinatorial libraries. Tetrahedron Letters, 2001, 42: 7119-7121
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