木果楝种子、果皮的化学成分研究及欧亚旋覆花中活性成分制备及其衍生物的合成
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摘要
第一部分木果楝种子化学成分研究
楝科木果楝属植物（Xylocarpus）为广泛分布于东南亚、澳洲、东非和印度沿海地带的红树林植物，本属包括三种植物分别为：Xylocarpusgranatum Koenig、Xylocarpus moluccensis和Xylocarpus rumphii，其中木果楝（X. granatum）在东南亚和印度作为民间药物，用来治疗痢疾、霍乱、发热以及用做抗虫剂，在我国只有海南省有生长。已报道木果楝（X.granatum）含有各种化学成分约110个，包括萜类、生物碱类、多酚类、黄酮类、甾体类和其他类，其中90多个为柠檬苦素类化合物，柠檬苦素类化合物是该植物中非常重要的一类化学成分。柠檬苦素是一类高度氧化的四降三萜化合物，有很多生物活性如：细胞毒、抗虫、抗菌活性以及止泻等。本课题对木果楝（X. granatum）种子的化学成分进行研究。
目的：以木果楝种子为研究对象，利用各种分类手段得到单体化合物，用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构，筛选单体化合物的生物活性。为发现新的药物先导化合物奠定基础。
方法：取粉碎后的药材约21Kg，用95%乙醇冷浸提取，每次浸泡时间为一周，提取3次。提取液过滤，减压浓缩至膏状，得浸膏约1000g。将浸膏悬浮于水中，分别用石油醚、二氯甲烷和乙酸乙酯萃取，萃取液减压浓缩，得到石油醚部分浸膏（60g）、二氯甲烷部分浸膏（485g）和乙酸乙酯部分浸膏（25g）。采用硅胶柱层析、葡聚糖凝胶、制备薄层法和制备高效液相色谱法对以上部位的化学成分进行分离，得到的单体化合物采用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构。
结果：从木果楝（X. granatum）种子中分离得到79个化合物，鉴定了其中48个化合物，结构鉴定结果如下：
9-trans-hexadecenoic acid (1), stigmasterol (2),3-oxo-4,22-choladienicacid (3), grantumin C (4), xylocarpin H (5), xylomexicanin A (6), cipadesin A(7), xyloccensin K (8), piscidinol G (9), xylogranatin C (10),hainangranatumin C (11), xylogranatin D (12), xylocartin S (13), xylocartin A(14), xylocartin B (15), hainangranatumin A (16), xylocarpin G (17),hydroxydammarenone-Ⅱ (18), xylocartin T (19), xylocartin N (22),xylocartin O (25), febrifugin (26), tigloylseneganolide A (27), khaysin T (28),cipadesin (29), granatumin B (30), xylocartin M (32), xylocartin C (37),bis(2-ethylhexyl) phthalate (38), xylocartin E (40), xylocartin D (41),xylocartin Q (44), xylocartin R (46), xylocartin F (47), xyloccensin S (48),granaxylocarpin C (54), xylogranatin E2(56), xylocartin P (60), xylocartin J(62), xyloccensin Q (64), xylocartin K (65), xylocartin G (67), xyloccensin P(68), xylocartin H (72), cedrodorin (73), xylorumphiins D (75), xylocartin L(77), xylocartin I (79)。
化合物10对非小细胞肺癌细胞（A549、RERF-LC-KJ和QG-56）、人小细胞肺癌细胞（PC-6）、人前列腺癌细胞株（PC-3）5种实验用细胞的增殖显示强于阳性对照顺铂的抑制活性，IC50分别为2.16、1.26、7.21、8.99和16.86μmol·L~(-1)；
结论：本研究对木果楝种子的化学成分进行了系统研究，分离鉴定的48个单体化合物中：其中20个为新化合物分别命名为xylocartins A-T，即化合物13、14、15、19、22、25、32、37、40、41、44、46、47、60、62、65、67、72、77、79；5个化合物为该属中首次发现，分别为化合物7、18、29、38、73；化合物75为该植物中首次发现的化合物。化合物10对癌细胞有抑制活性。
第二部分木果楝果皮化学成分研究
目的：以木果楝果皮为研究对象，利用各种分类手段得到单体化合物，用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构，筛选单体化合物的生物活性。为发现新的药物先导化合物奠定基础。
方法：取粉碎后的药材约13Kg，用95%乙醇冷浸提取，每次浸泡时间为一周，提取3次。提取液过滤，减压浓缩至膏状，得浸膏约500g。将浸膏悬浮于水中，分别用石油醚和乙酸乙酯萃取，萃取液减压浓缩，得到石油醚部分浸膏（30g）和乙酸乙酯部分浸膏（225g）。采用硅胶柱层析、葡聚糖凝胶、制备薄层法和制备高效液相色谱法对以上部位的化学成分进行分离，得到的单体化合物采用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1HCOSY、HMQC和HMBC鉴定化合物结构。
结果：从木果楝（X. granatum）果皮中分离鉴定了4个化合物，结构鉴定结果如下：β-谷甾醇(1)，3-oxo-4,22-choladienic acid (2)，xylocarpin H(3)，xyloccensin K (4)。
结论：本研究对木果楝果皮的化学成分进行了系统研究，分离鉴定的4个单体化合物中，3-oxo-4,22-choladienic acid (2)为首次从该属中分离得到的化合物。
第三部分CO_2超临界制备ABL及其衍生物的合成
目的：采用超临界流体萃取法提取欧亚旋覆花中的活性成分ABL，优化超临界流体萃取条件。将CO_2超临界流体萃取物，采用硅胶柱层析法进行分离，得到ABL单体。并以ABL为原料合成有抗肿瘤活性的衍生物NABL。
方法：以ABL含量为指标优化超临界流体萃取条件，对欧亚旋覆花干燥花10Kg，用优选的SFE萃取条件进行萃取，得到355g萃取物，采用硅胶柱色谱分离，得到ABL，通过酯化反应合成衍生物NABL。测定其对各种肿瘤细胞的抑制活性。
结果：优化了超临界流体萃取法提取条件：温度60℃，压力25.0Mpa，CO_2流量10L/min。用SFE萃取法和硅胶柱层析法得到ABL40g，合成衍生物40g，NABL对HT-29、K111、L1210以及3LL肿瘤细胞的增殖抑制活性优于顺铂。
结论：本研究建立了用CO_2超临界提取方法提取欧亚旋覆花中活性成分ABL的方法，以ABL为原料，合成具有抗肿瘤活性衍生物NABL，为NABL的体内药理实验提供样品。
Part one Chemical study on the components of Xylocarpus granatumseeds
The genus Xylocarpus, distributed widely in the coastal areas of South-East Asia, Australia, East Africa, and Indian Ocean, comprises only threespecies of the Meliaceae family. Xylocarpus granatum Koenig and Xylocarpusmoluccensis (Lam) are the most popular plants in empirical study, and arefound to be rich in limonoids. The mangrove plant X. granatum Koenig isused as a folk medicine in Southeast Asia and Indian for the treatment ofdiarrhea, cholera, and fever diseases such as malaria, and also as anantifeedant. Since the first limonoid, gedunin, was reported from this plant, theunique structural patterns of limonoids have attracted considerable attentionfrom medicinal chemists as well as chemical biologists because of theirfascinating structural diversity and wide spectral of biological activities. As aresult, more than50limonoid derivatives have been isolated from X. granatum,and they have been classified into phragmalin-, mexicanolide-, obacunol-, andandirobin-types. Recently, much attention has been paid to Xylocarpus speciesdue to limonoids with unique C-skeletons and their tumor cytotoxic activities.
Objective: To study the components in seeds of X. granatum, manymethods are used in the isolation and purification of the components. Thestructures of the pure compounds were elucidated by means of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC, etc. To exploid theactive constituents for tumor cells by activity screen.
Methods: Dried seeds (21kg) of X. granatum were extracted with95%ethanol at room temperature. After evaporation of the solvent under reducedpressure, the residue was suspended in water and extracted with petroleum ether, dichloromethane and ethyl acetate in order, successively. The isolationand purification were carried out by silica gel column chromatography,Sephadex, preparative TLC and preparative HPLC. The structures of theisolated compounds were identified with the help of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC techniques.
Results: Forty-eight compounds were isolated and elucidated from theseeds of X. granatum, their structures were identified as:
9-trans-hexadecenoic acid (1), stigmasterol (2),3-oxo-4,22-choladienicacid (3), grantumin C (4), xylocarpin H (5), xylomexicanin A (6), cipadesin A(7), xyloccensin K (8), piscidinol G (9), xylogranatin C (10),hainangranatumin C (11), xylogranatin D (12), xylocartin S (13), xylocartin A(14), xylocartin B (15), hainangranatumin A (16), xylocarpin G (17),hydroxydammarenone-Ⅱ (18), xylocartin T (19), xylocartin N (22), xylocartinO (25), febrifugin (26), tigloylseneganolide A (27), khaysin T (28), cipadesin(29), granatumin B (30), xylocartin M (32), xylocartin C (37),bis(2-ethylhexyl) phthalate)(38), xylocartin E (40), xylocartin D (41),xylocartin Q (44), xylocartin R (46), xylocartin F (47), xyloccensin S (48),granaxylocarpin C (54), xylogranatin E2(56), xylocartin P (60), xylocartin J(62), xyloccensin Q (64), xylocartin K (65), xylocartin G (67), xyloccensin P(68), xylocartin H (72), cedrodorin (73), xylorumphiins D (75), xylocartin L(77), xylocartin I (79)。
Conclusion: We investigated the constituents of the seeds of X. granatum,48compounds were isolated and elucidated, and among them xylocartins A-Twere20new compounds.
Part Two Chemical study on the components of Xylocarpus granatumpericarps
Objective: To study the components in pericarps of X. granatum, manymethods are used in the isolation and purification of the components. Thestructures of the pure compounds were elucidated by means of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC, etc. To identify active constituents by activity screen.
Methods: Dried pericarps (13kg) of X. granatum were extracted with95%ethanol at room temperature. After evaporation of the solvent underreduced pressure, the residue was suspended in water and extracted withpetroleum ether and dichloromethane, successively. The isolation andpurification were carried out by silica gel column chromatography, Sephadex,preparative TLC and preparative HPLC. The structures of the compoundswere elucidated with the help of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1HCOSY, HMQC and HMBC techniques.
Results: Four compounds were isolated and elucidated from thepericarps of X. granatum: β-sitosterol (1),3-oxo-4,22-choladienic acid (2),xylocarpin H (3), xyloccensin K (4)
Conclusion: The constituents of the pericarps of X. granatum wereinvestigated, four compounds were isolated and elucidated, among them3-oxo-4,22-choladienic acid (2) was found from this genus for the first time.
Part three Preparation of ABL by SFE and semi-synthesis of derivativesof ABL
Objective: To extract the active component ABL from Inula britannica Lby SFE with optimized conditions. The extraction was isolated to obtain ABL,which was used to synthesize the active derivatives.
Methods: Air-dried flowers of Inula britannica L (10Kg) were extractedby SFE, which conditions were optimized to obtain the extraction (355g). Theextraction were isolated and purified by silica gel chromatography to obtainABL, which was used to synthesize the active derivatives NABL. Theanti-tumor activities were screened on many cell lines.
Results: The optimized conditions of SFE was temperature:60℃,pressure:25.0Mpa, flow rate of CO_2:10L/min.40g NABL were synthesized,which anti-tumor activities were better than Cisplatin to HT-29, K111, L1210and3LL cell lines.
Conclusion: This research work established the method to used SFE to extract the active component ABL from Inula britannica L. The derivativeNABL was used to do the further investigation on in vivo pharmacologyexperiments.
楝科木果楝属植物（Xylocarpus）为广泛分布于东南亚、澳洲、东非和印度沿海地带的红树林植物，本属包括三种植物分别为：Xylocarpusgranatum Koenig、Xylocarpus moluccensis和Xylocarpus rumphii，其中木果楝（X. granatum）在东南亚和印度作为民间药物，用来治疗痢疾、霍乱、发热以及用做抗虫剂，在我国只有海南省有生长。已报道木果楝（X.granatum）含有各种化学成分约110个，包括萜类、生物碱类、多酚类、黄酮类、甾体类和其他类，其中90多个为柠檬苦素类化合物，柠檬苦素类化合物是该植物中非常重要的一类化学成分。柠檬苦素是一类高度氧化的四降三萜化合物，有很多生物活性如：细胞毒、抗虫、抗菌活性以及止泻等。本课题对木果楝（X. granatum）种子的化学成分进行研究。
目的：以木果楝种子为研究对象，利用各种分类手段得到单体化合物，用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构，筛选单体化合物的生物活性。为发现新的药物先导化合物奠定基础。
方法：取粉碎后的药材约21Kg，用95%乙醇冷浸提取，每次浸泡时间为一周，提取3次。提取液过滤，减压浓缩至膏状，得浸膏约1000g。将浸膏悬浮于水中，分别用石油醚、二氯甲烷和乙酸乙酯萃取，萃取液减压浓缩，得到石油醚部分浸膏（60g）、二氯甲烷部分浸膏（485g）和乙酸乙酯部分浸膏（25g）。采用硅胶柱层析、葡聚糖凝胶、制备薄层法和制备高效液相色谱法对以上部位的化学成分进行分离，得到的单体化合物采用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构。
结果：从木果楝（X. granatum）种子中分离得到79个化合物，鉴定了其中48个化合物，结构鉴定结果如下：
9-trans-hexadecenoic acid (1), stigmasterol (2),3-oxo-4,22-choladienicacid (3), grantumin C (4), xylocarpin H (5), xylomexicanin A (6), cipadesin A(7), xyloccensin K (8), piscidinol G (9), xylogranatin C (10),hainangranatumin C (11), xylogranatin D (12), xylocartin S (13), xylocartin A(14), xylocartin B (15), hainangranatumin A (16), xylocarpin G (17),hydroxydammarenone-Ⅱ (18), xylocartin T (19), xylocartin N (22),xylocartin O (25), febrifugin (26), tigloylseneganolide A (27), khaysin T (28),cipadesin (29), granatumin B (30), xylocartin M (32), xylocartin C (37),bis(2-ethylhexyl) phthalate (38), xylocartin E (40), xylocartin D (41),xylocartin Q (44), xylocartin R (46), xylocartin F (47), xyloccensin S (48),granaxylocarpin C (54), xylogranatin E2(56), xylocartin P (60), xylocartin J(62), xyloccensin Q (64), xylocartin K (65), xylocartin G (67), xyloccensin P(68), xylocartin H (72), cedrodorin (73), xylorumphiins D (75), xylocartin L(77), xylocartin I (79)。
化合物10对非小细胞肺癌细胞（A549、RERF-LC-KJ和QG-56）、人小细胞肺癌细胞（PC-6）、人前列腺癌细胞株（PC-3）5种实验用细胞的增殖显示强于阳性对照顺铂的抑制活性，IC50分别为2.16、1.26、7.21、8.99和16.86μmol·L~(-1)；
结论：本研究对木果楝种子的化学成分进行了系统研究，分离鉴定的48个单体化合物中：其中20个为新化合物分别命名为xylocartins A-T，即化合物13、14、15、19、22、25、32、37、40、41、44、46、47、60、62、65、67、72、77、79；5个化合物为该属中首次发现，分别为化合物7、18、29、38、73；化合物75为该植物中首次发现的化合物。化合物10对癌细胞有抑制活性。
第二部分木果楝果皮化学成分研究
目的：以木果楝果皮为研究对象，利用各种分类手段得到单体化合物，用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1H COSY、HMQC和HMBC鉴定化合物结构，筛选单体化合物的生物活性。为发现新的药物先导化合物奠定基础。
方法：取粉碎后的药材约13Kg，用95%乙醇冷浸提取，每次浸泡时间为一周，提取3次。提取液过滤，减压浓缩至膏状，得浸膏约500g。将浸膏悬浮于水中，分别用石油醚和乙酸乙酯萃取，萃取液减压浓缩，得到石油醚部分浸膏（30g）和乙酸乙酯部分浸膏（225g）。采用硅胶柱层析、葡聚糖凝胶、制备薄层法和制备高效液相色谱法对以上部位的化学成分进行分离，得到的单体化合物采用HR-ESI-MS、~1H NMR、~(13)C NMR、~1H-~1HCOSY、HMQC和HMBC鉴定化合物结构。
结果：从木果楝（X. granatum）果皮中分离鉴定了4个化合物，结构鉴定结果如下：β-谷甾醇(1)，3-oxo-4,22-choladienic acid (2)，xylocarpin H(3)，xyloccensin K (4)。
结论：本研究对木果楝果皮的化学成分进行了系统研究，分离鉴定的4个单体化合物中，3-oxo-4,22-choladienic acid (2)为首次从该属中分离得到的化合物。
第三部分CO_2超临界制备ABL及其衍生物的合成
目的：采用超临界流体萃取法提取欧亚旋覆花中的活性成分ABL，优化超临界流体萃取条件。将CO_2超临界流体萃取物，采用硅胶柱层析法进行分离，得到ABL单体。并以ABL为原料合成有抗肿瘤活性的衍生物NABL。
方法：以ABL含量为指标优化超临界流体萃取条件，对欧亚旋覆花干燥花10Kg，用优选的SFE萃取条件进行萃取，得到355g萃取物，采用硅胶柱色谱分离，得到ABL，通过酯化反应合成衍生物NABL。测定其对各种肿瘤细胞的抑制活性。
结果：优化了超临界流体萃取法提取条件：温度60℃，压力25.0Mpa，CO_2流量10L/min。用SFE萃取法和硅胶柱层析法得到ABL40g，合成衍生物40g，NABL对HT-29、K111、L1210以及3LL肿瘤细胞的增殖抑制活性优于顺铂。
结论：本研究建立了用CO_2超临界提取方法提取欧亚旋覆花中活性成分ABL的方法，以ABL为原料，合成具有抗肿瘤活性衍生物NABL，为NABL的体内药理实验提供样品。
Part one Chemical study on the components of Xylocarpus granatumseeds
The genus Xylocarpus, distributed widely in the coastal areas of South-East Asia, Australia, East Africa, and Indian Ocean, comprises only threespecies of the Meliaceae family. Xylocarpus granatum Koenig and Xylocarpusmoluccensis (Lam) are the most popular plants in empirical study, and arefound to be rich in limonoids. The mangrove plant X. granatum Koenig isused as a folk medicine in Southeast Asia and Indian for the treatment ofdiarrhea, cholera, and fever diseases such as malaria, and also as anantifeedant. Since the first limonoid, gedunin, was reported from this plant, theunique structural patterns of limonoids have attracted considerable attentionfrom medicinal chemists as well as chemical biologists because of theirfascinating structural diversity and wide spectral of biological activities. As aresult, more than50limonoid derivatives have been isolated from X. granatum,and they have been classified into phragmalin-, mexicanolide-, obacunol-, andandirobin-types. Recently, much attention has been paid to Xylocarpus speciesdue to limonoids with unique C-skeletons and their tumor cytotoxic activities.
Objective: To study the components in seeds of X. granatum, manymethods are used in the isolation and purification of the components. Thestructures of the pure compounds were elucidated by means of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC, etc. To exploid theactive constituents for tumor cells by activity screen.
Methods: Dried seeds (21kg) of X. granatum were extracted with95%ethanol at room temperature. After evaporation of the solvent under reducedpressure, the residue was suspended in water and extracted with petroleum ether, dichloromethane and ethyl acetate in order, successively. The isolationand purification were carried out by silica gel column chromatography,Sephadex, preparative TLC and preparative HPLC. The structures of theisolated compounds were identified with the help of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC techniques.
Results: Forty-eight compounds were isolated and elucidated from theseeds of X. granatum, their structures were identified as:
9-trans-hexadecenoic acid (1), stigmasterol (2),3-oxo-4,22-choladienicacid (3), grantumin C (4), xylocarpin H (5), xylomexicanin A (6), cipadesin A(7), xyloccensin K (8), piscidinol G (9), xylogranatin C (10),hainangranatumin C (11), xylogranatin D (12), xylocartin S (13), xylocartin A(14), xylocartin B (15), hainangranatumin A (16), xylocarpin G (17),hydroxydammarenone-Ⅱ (18), xylocartin T (19), xylocartin N (22), xylocartinO (25), febrifugin (26), tigloylseneganolide A (27), khaysin T (28), cipadesin(29), granatumin B (30), xylocartin M (32), xylocartin C (37),bis(2-ethylhexyl) phthalate)(38), xylocartin E (40), xylocartin D (41),xylocartin Q (44), xylocartin R (46), xylocartin F (47), xyloccensin S (48),granaxylocarpin C (54), xylogranatin E2(56), xylocartin P (60), xylocartin J(62), xyloccensin Q (64), xylocartin K (65), xylocartin G (67), xyloccensin P(68), xylocartin H (72), cedrodorin (73), xylorumphiins D (75), xylocartin L(77), xylocartin I (79)。
Conclusion: We investigated the constituents of the seeds of X. granatum,48compounds were isolated and elucidated, and among them xylocartins A-Twere20new compounds.
Part Two Chemical study on the components of Xylocarpus granatumpericarps
Objective: To study the components in pericarps of X. granatum, manymethods are used in the isolation and purification of the components. Thestructures of the pure compounds were elucidated by means of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1H COSY, HMQC and HMBC, etc. To identify active constituents by activity screen.
Methods: Dried pericarps (13kg) of X. granatum were extracted with95%ethanol at room temperature. After evaporation of the solvent underreduced pressure, the residue was suspended in water and extracted withpetroleum ether and dichloromethane, successively. The isolation andpurification were carried out by silica gel column chromatography, Sephadex,preparative TLC and preparative HPLC. The structures of the compoundswere elucidated with the help of HR-ESI-MS,~1H NMR,~(13)C NMR,~1H-~1HCOSY, HMQC and HMBC techniques.
Results: Four compounds were isolated and elucidated from thepericarps of X. granatum: β-sitosterol (1),3-oxo-4,22-choladienic acid (2),xylocarpin H (3), xyloccensin K (4)
Conclusion: The constituents of the pericarps of X. granatum wereinvestigated, four compounds were isolated and elucidated, among them3-oxo-4,22-choladienic acid (2) was found from this genus for the first time.
Part three Preparation of ABL by SFE and semi-synthesis of derivativesof ABL
Objective: To extract the active component ABL from Inula britannica Lby SFE with optimized conditions. The extraction was isolated to obtain ABL,which was used to synthesize the active derivatives.
Methods: Air-dried flowers of Inula britannica L (10Kg) were extractedby SFE, which conditions were optimized to obtain the extraction (355g). Theextraction were isolated and purified by silica gel chromatography to obtainABL, which was used to synthesize the active derivatives NABL. Theanti-tumor activities were screened on many cell lines.
Results: The optimized conditions of SFE was temperature:60℃,pressure:25.0Mpa, flow rate of CO_2:10L/min.40g NABL were synthesized,which anti-tumor activities were better than Cisplatin to HT-29, K111, L1210and3LL cell lines.
Conclusion: This research work established the method to used SFE to extract the active component ABL from Inula britannica L. The derivativeNABL was used to do the further investigation on in vivo pharmacologyexperiments.
引文
1Mulholland DA, Taylor DAH, Limonoids from Australian members of theMeliaceae. Phytochemistry,1992,31:4163-4166
2Champagne DE, Koul O, Isman MB, et al. Biological activity of limonoidsfrom Rutales. Phytochemistry,1992,31:377-394
3Taylor DAH, Limonoid extractives from Xylocarpus moluccensis.Phytochemistry,1983,22:1297-1299
4Taylor DAH, Extractives from East African timbers. J. Chem. Soc.,1965,3495-3496
5Ng AS, Fallis AG,7-Acetoxydihydronomilin and mexicanolide: limonoidsfrom Xylocarpus granatum (Koenig). Can. J. Chem.,1979,57:3088-3089
6Alvi KA, Crews P, Aalbersberg B, et al. Limonoids from the fijianmedicinal plant dabi (xylocarpus). Tetrahedron,1991,47:8943-8948
7Okorie DA, Taylor DAH, Limonoids from Xylocarpus granatum Koenig. J.Chem. Soc. C,1970:211-213
8Connolly JD, Maclellan M, Okorie DA et al. Limonoids from Xylocarpusmoluccensis (lam). J. Chem. Soc., Perkin Trans.1976,1:1093-1096
9Yin S, Wang XN, Fan CQ et al. Limonoids from the Seeds of the MarineMangrove Xylocarpus granatum. J. Nat. Prod.,2007,70:682-685
10Yin S, Fan CQ, Wang XN, et al. Xylogranatins AD: NovelTetranortriterpenoids with an Unusual9,10-s eco Scaffold from MarineMangrove Xylocarpus g ranatum. Org. Lett.,2006,8:4935-4938
11Chou FY, Hostettmann K, Kubo I, et al. Isolation of an insect antifeedantN-methylflindersine and several benz[c]phenanthridine alkaloids from EastAfrican plants; a comment on chelerythrine. Heterocycles,1977,7:969-977
12Kubo I, Miura I, Nakanishi K, The structure of xylomollin, a secoiridoidhemiacetal acetal. J. Am. Chem. Soc.,1976,98:6704-6705
13戴好富，梅文莉，洪葵，等海南16种红树植物的肿瘤细胞毒活性筛选。中国海洋药物,2005,24:44-48
14Stephen WA, Raymond J. Andersen Steroidal antifeedants from the doridnudibranch aldisa sanguinea cooperi. Tetrahedron Letters,1982,23:1039-1042
15Shen LR, Dong M, Guo D et al. Xylomexicanins A and B, new|¤14,15-mexicanolides from seeds of the Chinese mangrove Xylocarpusgranatum. Z. Naturforsch. C,2009,64:37-42.
16Sarigaputi C, Nuanyai T, Teerawatananond T et al. Xylorumphiins A-D,Mexicanolide Limonoids from the Seed Kernels of Xylocarpus rumphii. J.Nat. Prod.,2010,73:1456-1459.
17Cui J, Deng Z, Li J et al. Phragmalin-type limonoids from the mangroveplant Xylocarpus granatum. Phytochemistry,2005,66:2334-2339
18Li MY, Yang XB, Pan JY, et al. Granatumins A-G, Limonoids from theSeeds of a Krishna Mangrove, Xylocarpus granatum. J. Nat. Prod.,2009,72:2110-2114
19Yin S, Fan CQ, Wang XN, et al. Xylogranatins AD: NovelTetranortriterpenoids with an Unusual9,10-seco Scaffold from MarineMangrove Xylocarpus granatum. Organic Letters,2006,8:4935-4938
20Pan JY, Chen SL, Li MY, et al. Limonoids from the Seeds of a HainanMangrove, Xylocarpus granatum. J. Nat. Prod.,2010,73:1672-1679
21Wu J, Li M, Zhang S, et al. Two New Limonoids with a3-O-beta-TigloylGroup from the Seeds of the Chinese Mangrove Xylocarpus granatum.Zeitschrift Fur Naturforschung B,2007,62:859-863
22Veitch NC, Wright GA, Stevenson PC, Four new tetranortriterpenoids fromCedrela odorata associated with leaf rejection by Exopthalmus jekelianus.J. Nat. Prod.,1999,62:1260-1263
23Luo XD, Wu SH, Ma YB, et al. Components of Cipadessa baccifera.Phytochemistry,2000,55:867-872
24Zhang F, Wang JS, Gu YC, et al. Cytotoxic and Anti-inflammatoryTriterpenoids from Toona ciliate. J. Nat. Prod.,2012,75:538-546
25Gan LS, Wang XN, Wu Y, et al. Tetranortriterpenoids from Cipadessabaccifera. J. Nat. Prod.,2007,70:1344-1347
26Adesogan EK, Taylor DAH, Extractives from Khaya senagalensis. Journalof the Chemical Society [Section] C: Organic1968,16:1974-1981
1Mulholland DA, Taylor DAH, Limonoids from Australian members of theMeliaceae. Phytochemistry,1992,31:4163-4166
2Champagne DE, Koul O, Isman MB, et al. Biological activity of limonoidsfrom Rutales. Phytochemistry,1992,31:377-394
3Taylor DAH, Limonoid extractives from Xylocarpus moluccensis.Phytochemistry,1983,22:1297-1299
4Taylor DAH, Extractives from East African timbers. J. Chem. Soc.,1965,3495-3496
5Ng AS, Fallis AG,7-Acetoxydihydronomilin and mexicanolide: limonoidsfrom Xylocarpus granatum (Koenig). Can. J. Chem.,1979,57:3088-3089
6Alvi KA, Crews P, Aalbersberg B, et al. Limonoids from the fijianmedicinal plant dabi (xylocarpus). Tetrahedron,1991,47:8943-8948
7Okorie DA, Taylor DAH, Limonoids from Xylocarpus granatum Koenig. J.Chem. Soc. C,1970,211-213
8Connolly JD, Maclellan M, Okorie DA et al. Limonoids from Xylocarpusmoluccensis (lam). J. Chem. Soc., Perkin Trans.1976,1:1093-1096
9Yin S, Wang XN, Fan CQ et al, Limonoids from the Seeds of the MarineMangrove Xylocarpus granatum. J. Nat. Prod.,2007,70:682-685
10Yin S, Fan CQ, Wang XN, et al. Xylogranatins A-D: NovelTetranortriterpenoids with an unusual9,10-s eco scaffold from marinemangrove Xylocarpus g ranatum. Org. Lett.,2006,8:4935-4938
11Chou FY, Hostettmann K, Kubo I, et al. Isolation of an insect antifeedantN-methylflindersine and several benz[c]phenanthridine alkaloids fromEast African plants; a comment on chelerythrine. Heterocycles,1977,7:969-977
12Kubo I, Miura I, Nakanishi K, The structure of xylomollin, a secoiridoidhemiacetal acetal. J. Am. Chem. Soc.,1976,98:6704-6705
13戴好富，梅文莉，洪葵，等海南16种红树植物的肿瘤细胞毒活性筛选。中国海洋药物,2005,24:44-48
14Stephen W. Ayer, Raymond J. Andersen Steroidal antifeedants from thedorid nudibranch aldisa sanguinea cooperi. Tetrahedron Letters,1982,23:1039-1042
1Iijima K, Kiyohara H, Tanaka M, et al. Preventive effect of taraxasterylacetate from Inula Britannica L. subsp. Japonica on experimental hepatitisin vivo. Planta Med,1995,61:50-53.
2Shashi B, Mahato, Asish P, et al. CNMR Spectra of pentacyclictriterpennoids－a compilation and some salient features. Phytochemistry,1994,37:1517-1575.
3Han JW, Lee BG, Kim YK, et al. Ergolide, sesquiterpene lactone fromInula Britannica L., inhibits inducible nitric oxide synthase andcyclo-oxygenase-2expression in RAW264.7macrophages through theinactivation of NF-κB. British Journal of Pharmacology,2001,133:503-512.
1Chau R, Kalaitzis J A, Neilan B A. On the origins and biosynthesis oftetrodotoxin [J]. Aquatic Toxicology,2011,104:1-2.
2Clark R F, Williams S R, Nordt S P, et al. A review of selected seafoodpoisonings [J]. Undersea Hyperb Med,1999,26(3):175-84.
3平田义正.天然物有机化学[M].岩波书店（东京），1981,1-308.
4Skye K, Azadeh F. Tetrodotoxin and Maculotoxin [M]. University of NewMexico,2007,9.
5Material Safety Data Sheet Tetrodotoxin. Sigma-Aldrich Version1.6updated10March2007.
6Hwang DF, Noguchi T. Tetrodotoxin poisoning [J]. Adv Food Nutr Res,2007,52:141-236.
7Hagen NA, du SP, Lapointe B, et al. Tetrodotoxin for moderate to severecancer pain: A randomized, double blind, parallel design multicenter study[J]. J Pain Symptom Manage,2008,35(4):420-429.
8Kishi Y, Aratani M, Fukuyama T, et al. Synthetic studies on tetrodotoxinand related compounds.3. A stereospecific synthesis of an equivalent ofacetylated tetrodamine [J]. J Am Chem Soc,1972,94(26):9217-9219.
9Kishi Y, Fukuyama T, Aratani M, et al. Synthetic studies on tetrodotoxinand related compounds. IV. Stereospecific total syntheses of DL-tetrodotoxin [J]. J Am Chem Soc,1972,94(26):9219-9221.
10Ohyabu N, Nishikawa T, Isobe M. First asymmetric total synthesis oftetrodotoxin [J]. J Am Chem Soc,2003,125(29):8798-8805.
11Nishikawa T, Urabe D, Isobe M. An efficient total synthesis of opticallyactive tetrodotoxin [J]. Angewandte Chemie International Edition,2004,43(36):4782-4785.
12Sato K, Asak S, Sugita N, et al. Novel and stereocontrolled synthesis of(±)-tetrodotoxin from myo-inositol. J.Org.Chem.,2005,70(20):7496-7504.
2Champagne DE, Koul O, Isman MB, et al. Biological activity of limonoidsfrom Rutales. Phytochemistry,1992,31:377-394
3Taylor DAH, Limonoid extractives from Xylocarpus moluccensis.Phytochemistry,1983,22:1297-1299
4Taylor DAH, Extractives from East African timbers. J. Chem. Soc.,1965,3495-3496
5Ng AS, Fallis AG,7-Acetoxydihydronomilin and mexicanolide: limonoidsfrom Xylocarpus granatum (Koenig). Can. J. Chem.,1979,57:3088-3089
6Alvi KA, Crews P, Aalbersberg B, et al. Limonoids from the fijianmedicinal plant dabi (xylocarpus). Tetrahedron,1991,47:8943-8948
7Okorie DA, Taylor DAH, Limonoids from Xylocarpus granatum Koenig. J.Chem. Soc. C,1970:211-213
8Connolly JD, Maclellan M, Okorie DA et al. Limonoids from Xylocarpusmoluccensis (lam). J. Chem. Soc., Perkin Trans.1976,1:1093-1096
9Yin S, Wang XN, Fan CQ et al. Limonoids from the Seeds of the MarineMangrove Xylocarpus granatum. J. Nat. Prod.,2007,70:682-685
10Yin S, Fan CQ, Wang XN, et al. Xylogranatins AD: NovelTetranortriterpenoids with an Unusual9,10-s eco Scaffold from MarineMangrove Xylocarpus g ranatum. Org. Lett.,2006,8:4935-4938
11Chou FY, Hostettmann K, Kubo I, et al. Isolation of an insect antifeedantN-methylflindersine and several benz[c]phenanthridine alkaloids from EastAfrican plants; a comment on chelerythrine. Heterocycles,1977,7:969-977
12Kubo I, Miura I, Nakanishi K, The structure of xylomollin, a secoiridoidhemiacetal acetal. J. Am. Chem. Soc.,1976,98:6704-6705
13戴好富，梅文莉，洪葵，等海南16种红树植物的肿瘤细胞毒活性筛选。中国海洋药物,2005,24:44-48
14Stephen WA, Raymond J. Andersen Steroidal antifeedants from the doridnudibranch aldisa sanguinea cooperi. Tetrahedron Letters,1982,23:1039-1042
15Shen LR, Dong M, Guo D et al. Xylomexicanins A and B, new|¤14,15-mexicanolides from seeds of the Chinese mangrove Xylocarpusgranatum. Z. Naturforsch. C,2009,64:37-42.
16Sarigaputi C, Nuanyai T, Teerawatananond T et al. Xylorumphiins A-D,Mexicanolide Limonoids from the Seed Kernels of Xylocarpus rumphii. J.Nat. Prod.,2010,73:1456-1459.
17Cui J, Deng Z, Li J et al. Phragmalin-type limonoids from the mangroveplant Xylocarpus granatum. Phytochemistry,2005,66:2334-2339
18Li MY, Yang XB, Pan JY, et al. Granatumins A-G, Limonoids from theSeeds of a Krishna Mangrove, Xylocarpus granatum. J. Nat. Prod.,2009,72:2110-2114
19Yin S, Fan CQ, Wang XN, et al. Xylogranatins AD: NovelTetranortriterpenoids with an Unusual9,10-seco Scaffold from MarineMangrove Xylocarpus granatum. Organic Letters,2006,8:4935-4938
20Pan JY, Chen SL, Li MY, et al. Limonoids from the Seeds of a HainanMangrove, Xylocarpus granatum. J. Nat. Prod.,2010,73:1672-1679
21Wu J, Li M, Zhang S, et al. Two New Limonoids with a3-O-beta-TigloylGroup from the Seeds of the Chinese Mangrove Xylocarpus granatum.Zeitschrift Fur Naturforschung B,2007,62:859-863
22Veitch NC, Wright GA, Stevenson PC, Four new tetranortriterpenoids fromCedrela odorata associated with leaf rejection by Exopthalmus jekelianus.J. Nat. Prod.,1999,62:1260-1263
23Luo XD, Wu SH, Ma YB, et al. Components of Cipadessa baccifera.Phytochemistry,2000,55:867-872
24Zhang F, Wang JS, Gu YC, et al. Cytotoxic and Anti-inflammatoryTriterpenoids from Toona ciliate. J. Nat. Prod.,2012,75:538-546
25Gan LS, Wang XN, Wu Y, et al. Tetranortriterpenoids from Cipadessabaccifera. J. Nat. Prod.,2007,70:1344-1347
26Adesogan EK, Taylor DAH, Extractives from Khaya senagalensis. Journalof the Chemical Society [Section] C: Organic1968,16:1974-1981
1Mulholland DA, Taylor DAH, Limonoids from Australian members of theMeliaceae. Phytochemistry,1992,31:4163-4166
2Champagne DE, Koul O, Isman MB, et al. Biological activity of limonoidsfrom Rutales. Phytochemistry,1992,31:377-394
3Taylor DAH, Limonoid extractives from Xylocarpus moluccensis.Phytochemistry,1983,22:1297-1299
4Taylor DAH, Extractives from East African timbers. J. Chem. Soc.,1965,3495-3496
5Ng AS, Fallis AG,7-Acetoxydihydronomilin and mexicanolide: limonoidsfrom Xylocarpus granatum (Koenig). Can. J. Chem.,1979,57:3088-3089
6Alvi KA, Crews P, Aalbersberg B, et al. Limonoids from the fijianmedicinal plant dabi (xylocarpus). Tetrahedron,1991,47:8943-8948
7Okorie DA, Taylor DAH, Limonoids from Xylocarpus granatum Koenig. J.Chem. Soc. C,1970,211-213
8Connolly JD, Maclellan M, Okorie DA et al. Limonoids from Xylocarpusmoluccensis (lam). J. Chem. Soc., Perkin Trans.1976,1:1093-1096
9Yin S, Wang XN, Fan CQ et al, Limonoids from the Seeds of the MarineMangrove Xylocarpus granatum. J. Nat. Prod.,2007,70:682-685
10Yin S, Fan CQ, Wang XN, et al. Xylogranatins A-D: NovelTetranortriterpenoids with an unusual9,10-s eco scaffold from marinemangrove Xylocarpus g ranatum. Org. Lett.,2006,8:4935-4938
11Chou FY, Hostettmann K, Kubo I, et al. Isolation of an insect antifeedantN-methylflindersine and several benz[c]phenanthridine alkaloids fromEast African plants; a comment on chelerythrine. Heterocycles,1977,7:969-977
12Kubo I, Miura I, Nakanishi K, The structure of xylomollin, a secoiridoidhemiacetal acetal. J. Am. Chem. Soc.,1976,98:6704-6705
13戴好富，梅文莉，洪葵，等海南16种红树植物的肿瘤细胞毒活性筛选。中国海洋药物,2005,24:44-48
14Stephen W. Ayer, Raymond J. Andersen Steroidal antifeedants from thedorid nudibranch aldisa sanguinea cooperi. Tetrahedron Letters,1982,23:1039-1042
1Iijima K, Kiyohara H, Tanaka M, et al. Preventive effect of taraxasterylacetate from Inula Britannica L. subsp. Japonica on experimental hepatitisin vivo. Planta Med,1995,61:50-53.
2Shashi B, Mahato, Asish P, et al. CNMR Spectra of pentacyclictriterpennoids－a compilation and some salient features. Phytochemistry,1994,37:1517-1575.
3Han JW, Lee BG, Kim YK, et al. Ergolide, sesquiterpene lactone fromInula Britannica L., inhibits inducible nitric oxide synthase andcyclo-oxygenase-2expression in RAW264.7macrophages through theinactivation of NF-κB. British Journal of Pharmacology,2001,133:503-512.
1Chau R, Kalaitzis J A, Neilan B A. On the origins and biosynthesis oftetrodotoxin [J]. Aquatic Toxicology,2011,104:1-2.
2Clark R F, Williams S R, Nordt S P, et al. A review of selected seafoodpoisonings [J]. Undersea Hyperb Med,1999,26(3):175-84.
3平田义正.天然物有机化学[M].岩波书店（东京），1981,1-308.
4Skye K, Azadeh F. Tetrodotoxin and Maculotoxin [M]. University of NewMexico,2007,9.
5Material Safety Data Sheet Tetrodotoxin. Sigma-Aldrich Version1.6updated10March2007.
6Hwang DF, Noguchi T. Tetrodotoxin poisoning [J]. Adv Food Nutr Res,2007,52:141-236.
7Hagen NA, du SP, Lapointe B, et al. Tetrodotoxin for moderate to severecancer pain: A randomized, double blind, parallel design multicenter study[J]. J Pain Symptom Manage,2008,35(4):420-429.
8Kishi Y, Aratani M, Fukuyama T, et al. Synthetic studies on tetrodotoxinand related compounds.3. A stereospecific synthesis of an equivalent ofacetylated tetrodamine [J]. J Am Chem Soc,1972,94(26):9217-9219.
9Kishi Y, Fukuyama T, Aratani M, et al. Synthetic studies on tetrodotoxinand related compounds. IV. Stereospecific total syntheses of DL-tetrodotoxin [J]. J Am Chem Soc,1972,94(26):9219-9221.
10Ohyabu N, Nishikawa T, Isobe M. First asymmetric total synthesis oftetrodotoxin [J]. J Am Chem Soc,2003,125(29):8798-8805.
11Nishikawa T, Urabe D, Isobe M. An efficient total synthesis of opticallyactive tetrodotoxin [J]. Angewandte Chemie International Edition,2004,43(36):4782-4785.
12Sato K, Asak S, Sugita N, et al. Novel and stereocontrolled synthesis of(±)-tetrodotoxin from myo-inositol. J.Org.Chem.,2005,70(20):7496-7504.