飞蓬的化学成分分离和不对称联苯化合物的合成、活性及构效关系研究
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摘要
本论文的上篇研究了采自甘肃漳县的飞蓬的化学成分。菊科飞蓬属(Erigeron)植物,全属约有200种以上,我国有35种,主要分布于新疆及西南部山区,其中只有4种在民间长期入药,但功效各不相同。国内对该属植物的研究主要集中在短葶飞蓬[Erigeron breviscapus(Vant.)Hand-Mazz.](又名灯盏花)上,尤其是灯盏花的有效成分已被发掘,而且用于临床治疗偏瘫。飞蓬(Erigeron acer)属于飞蓬属的一个种,此种在我国分布极广,其药用价值以及化学成份未见报道。
论文中利用常规柱层析、制备薄层层析、重结晶等手段从飞蓬中分离得到多种类型的化合物32个,并用IR、MS、~1H-NMR、~(13)C-NMR、DEPT、2D-NMR、CD及旋光等光谱技术鉴定了28个化合物的结构。其中1个倍半萜、1个二萜糖苷及2个丁烯酸内酯类化合物为新化合物。
五味子(Schisandra chinensis)是传统中药中常用的滋补、收敛药。它的主要成分联苯环辛二烯类木脂素具有抗肿瘤、抗肝毒(肝脏受损)、抗痉挛、抗HIV、抗真菌等生物活性。20世纪70年代,我国临床研究中发现五味子能明显降低肝炎患者血清谷丙转氨酶(SGPT)的水平,从而引起了研究中药五味子的热潮,并由此研制出了治疗肝炎的药物联苯双酯和双环醇,而其中的联苯结构片段是这些具有药理活性的天然产物的一个重要的活性部位。
本论文的下篇合成了65个不对称联苯类化合物,同时对合成的化合物进行了活性评价及构效关系讨论。(1)活性评价:a)抗癌活性评价:采用的癌细胞为人肺癌细胞A549、人前列腺癌细胞PC-3、人前列腺癌细胞DU145、人口腔上皮癌细胞KB和具有耐药性的人口腔上皮癌细胞KBVIN等,GI_(50)值由SRB法测定,采用高三尖杉和依托泊苷为阳性对照。筛选结果显示:化合物48和51有着较强的抗癌活性,GI_(50)值为0.04μM,特别值得一提的是一些化合物(23,27,46,48,51,54)对于具有耐药性的人口腔上皮癌细胞KBVIN也显示出了较强的抑制活性。b)抗HIV活性性评价:我们对合成的20个化合物在MT-2淋巴细胞模型上进行了抗HIV的生物活性评价。部分化合物在H9细胞系试验中进行了测试。发现化合物8和46显示了一定的抗HIV活性,其TI值分别为14和16.6。(2)抗肿瘤活性构效关系分析:a)醛基是一个必要的活性基,且含有两个醛基的化合物的活性要好于含有一个醛基的化合物;b)大的酰化基团是保持较好活性的一个有利因素;c)分子中含有亚甲二氧基团是提高其抗肿瘤活性的一个有利因素,且亚甲二氧基团的位置不影响其抗肿瘤活性;d)六元环内酯比七元环内酯更有助于提高抗肿瘤活性。
论文的研究结果对植物分类和开发利用植物资源提供了化学成分方面的证据;对抗肿瘤、抗HIV药物的研究与开发提供了理论依据,具有应用价值。
In the first part of this thesis the chemical components of Erigeron acer collected in Zhangxian County, Gansu Province, were investigated. About 200 species belong to the Erigeron family (Compositae) in the world, of which 35 are distributed in China, mainly in Xinjiang and the mountains of Southwest China; only 4 species have been used as Chinese folk medicines. Much research has been done on Erigeron breviscapus by Chinese researchers due to its good bioactivities. Erigeron acer belongs to the Erigeron family, which is distributed extensively in China. There has been no report about its usefulness in medicine and its chemical components.
32 compounds with various structural types were isolated from Erigeron acer by means of silica gel column chromatography (CC), preparative thin layer chromatography (PTLC) and recrystalIization etc. The structures of 28 compounds were elucidated on the basis of spectroscopic methods (IR, MS, ~1H-NMR, ~(13)C-NMR, DEPT, 2D-NMR and CD, etc). Among them, one sesquiterpene, one diterpene glycoside and two butenolide derivatives are new compounds.
Schisandra chinensis is used as a tonic and astringent drug in traditional Chinese medicine. Its major constituents, dibenzocyclooctandiene lignans, exhibit antitumor, antihepatotoxic (liverinjury), anticonvulsive, anti-HIV and antifungal activities. In the 1970s, it was found in clinical studies that Schisandra chinensis could decrease SGPT, and this result attracted the attention of many scientists. 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (α-DDB) and bicyclol, which were obtained from Schisandra chinensis, are being developed as new medicines for hepatopathy, and the biphenyl structural unit of these natural products is crucial for their pharmacological activities.
The second part of this thesis described the synthesis of 65 unsymmetrical biphenyl derivatives, evaluated their activities and discussed their structure-activity relationship (SAR). (1) Activity evaluation: a) Antitumor activity: all the 65 compounds were assayed against A549, PC-3, DU145, KB, KBVIN cell lines to evaluate their antitumor activity. The values of GI50 were measured by SRB method with antitumor drugs homoharringtonine and etoposide as positive controls. The result showed that compounds 48 and 51 have good activity with GI50 value of 0.04μM against the above cell lines; especially, compounds 23, 27, 46, 48, 51, 54 showed good inhibitory activity against KBVIN which are resistant to other antitumor medicines, b) Anti-HIV activity: 20 compounds were assayed in MT-2 cell lines to evaluate their anti-HIV activity. Some compounds were evaluated in H9 cell lines. The results showed that 8 and 46 exhibited potent anti-HIV activity in MT-2 cell line with TI values of 14 and 16.6, respectively. (2) SAR analysis of antitumor activity: a) Aldehyde group is a necessary group and the activity of compounds with two aldehyde groups are better, b) A bigger acyl group is favorable for activity, c) The methlyenedioxy group in the molecular is useful for elevating the activity, but its position is irrespective of the activity, d) A six-member-ring lactone is more favorable than a seven-member-ring lactone in elevating the activity.
The results of this thesis offer phytochemical proofs for plant chemotaxonomy and for exploiting and utilizing natural resources; they also provide some theoreticalevidence to the research and development of antitumor and anti-HIV medicines.
论文中利用常规柱层析、制备薄层层析、重结晶等手段从飞蓬中分离得到多种类型的化合物32个,并用IR、MS、~1H-NMR、~(13)C-NMR、DEPT、2D-NMR、CD及旋光等光谱技术鉴定了28个化合物的结构。其中1个倍半萜、1个二萜糖苷及2个丁烯酸内酯类化合物为新化合物。
五味子(Schisandra chinensis)是传统中药中常用的滋补、收敛药。它的主要成分联苯环辛二烯类木脂素具有抗肿瘤、抗肝毒(肝脏受损)、抗痉挛、抗HIV、抗真菌等生物活性。20世纪70年代,我国临床研究中发现五味子能明显降低肝炎患者血清谷丙转氨酶(SGPT)的水平,从而引起了研究中药五味子的热潮,并由此研制出了治疗肝炎的药物联苯双酯和双环醇,而其中的联苯结构片段是这些具有药理活性的天然产物的一个重要的活性部位。
本论文的下篇合成了65个不对称联苯类化合物,同时对合成的化合物进行了活性评价及构效关系讨论。(1)活性评价:a)抗癌活性评价:采用的癌细胞为人肺癌细胞A549、人前列腺癌细胞PC-3、人前列腺癌细胞DU145、人口腔上皮癌细胞KB和具有耐药性的人口腔上皮癌细胞KBVIN等,GI_(50)值由SRB法测定,采用高三尖杉和依托泊苷为阳性对照。筛选结果显示:化合物48和51有着较强的抗癌活性,GI_(50)值为0.04μM,特别值得一提的是一些化合物(23,27,46,48,51,54)对于具有耐药性的人口腔上皮癌细胞KBVIN也显示出了较强的抑制活性。b)抗HIV活性性评价:我们对合成的20个化合物在MT-2淋巴细胞模型上进行了抗HIV的生物活性评价。部分化合物在H9细胞系试验中进行了测试。发现化合物8和46显示了一定的抗HIV活性,其TI值分别为14和16.6。(2)抗肿瘤活性构效关系分析:a)醛基是一个必要的活性基,且含有两个醛基的化合物的活性要好于含有一个醛基的化合物;b)大的酰化基团是保持较好活性的一个有利因素;c)分子中含有亚甲二氧基团是提高其抗肿瘤活性的一个有利因素,且亚甲二氧基团的位置不影响其抗肿瘤活性;d)六元环内酯比七元环内酯更有助于提高抗肿瘤活性。
论文的研究结果对植物分类和开发利用植物资源提供了化学成分方面的证据;对抗肿瘤、抗HIV药物的研究与开发提供了理论依据,具有应用价值。
In the first part of this thesis the chemical components of Erigeron acer collected in Zhangxian County, Gansu Province, were investigated. About 200 species belong to the Erigeron family (Compositae) in the world, of which 35 are distributed in China, mainly in Xinjiang and the mountains of Southwest China; only 4 species have been used as Chinese folk medicines. Much research has been done on Erigeron breviscapus by Chinese researchers due to its good bioactivities. Erigeron acer belongs to the Erigeron family, which is distributed extensively in China. There has been no report about its usefulness in medicine and its chemical components.
32 compounds with various structural types were isolated from Erigeron acer by means of silica gel column chromatography (CC), preparative thin layer chromatography (PTLC) and recrystalIization etc. The structures of 28 compounds were elucidated on the basis of spectroscopic methods (IR, MS, ~1H-NMR, ~(13)C-NMR, DEPT, 2D-NMR and CD, etc). Among them, one sesquiterpene, one diterpene glycoside and two butenolide derivatives are new compounds.
Schisandra chinensis is used as a tonic and astringent drug in traditional Chinese medicine. Its major constituents, dibenzocyclooctandiene lignans, exhibit antitumor, antihepatotoxic (liverinjury), anticonvulsive, anti-HIV and antifungal activities. In the 1970s, it was found in clinical studies that Schisandra chinensis could decrease SGPT, and this result attracted the attention of many scientists. 4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (α-DDB) and bicyclol, which were obtained from Schisandra chinensis, are being developed as new medicines for hepatopathy, and the biphenyl structural unit of these natural products is crucial for their pharmacological activities.
The second part of this thesis described the synthesis of 65 unsymmetrical biphenyl derivatives, evaluated their activities and discussed their structure-activity relationship (SAR). (1) Activity evaluation: a) Antitumor activity: all the 65 compounds were assayed against A549, PC-3, DU145, KB, KBVIN cell lines to evaluate their antitumor activity. The values of GI50 were measured by SRB method with antitumor drugs homoharringtonine and etoposide as positive controls. The result showed that compounds 48 and 51 have good activity with GI50 value of 0.04μM against the above cell lines; especially, compounds 23, 27, 46, 48, 51, 54 showed good inhibitory activity against KBVIN which are resistant to other antitumor medicines, b) Anti-HIV activity: 20 compounds were assayed in MT-2 cell lines to evaluate their anti-HIV activity. Some compounds were evaluated in H9 cell lines. The results showed that 8 and 46 exhibited potent anti-HIV activity in MT-2 cell line with TI values of 14 and 16.6, respectively. (2) SAR analysis of antitumor activity: a) Aldehyde group is a necessary group and the activity of compounds with two aldehyde groups are better, b) A bigger acyl group is favorable for activity, c) The methlyenedioxy group in the molecular is useful for elevating the activity, but its position is irrespective of the activity, d) A six-member-ring lactone is more favorable than a seven-member-ring lactone in elevating the activity.
The results of this thesis offer phytochemical proofs for plant chemotaxonomy and for exploiting and utilizing natural resources; they also provide some theoreticalevidence to the research and development of antitumor and anti-HIV medicines.
引文
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