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論文名稱 Title |
台灣產五味子科植物生物活性成分與山防風噻吩衍生物合成之研究 Studies on the Bioactive Constituents of Taiwanese Schisandraceous Plants and Synthesis of Thiophene Derivatives of Echinops grijsii |
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系所名稱 Department |
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畢業學年期 Year, semester |
語文別 Language |
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學位類別 Degree |
頁數 Number of pages |
213 |
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研究生 Author |
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指導教授 Advisor |
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召集委員 Convenor |
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口試委員 Advisory Committee |
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口試日期 Date of Exam |
2003-06-25 |
繳交日期 Date of Submission |
2003-07-08 |
關鍵字 Keywords |
木質酚素、噻吩、抗B型肝炎、抗癌 thiophene, anti-HBV, lignan, anti-tumor |
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統計 Statistics |
本論文已被瀏覽 5744 次,被下載 3462 次 The thesis/dissertation has been browsed 5744 times, has been downloaded 3462 times. |
中文摘要 |
中文摘要 癌為國人致死原因之首位,B型肝炎問題在台灣亦相當嚴重,實驗室在以往發展新的抗癌與抗肝炎病毒藥物中,發現台灣五味子科植物包含小本紅骨蛇、阿里山五味子與南五味子之酒精抽取物對B型肝炎病毒表面抗原和e抗原具抑制作用;而山防風則對人類癌細胞KB和Hela具抑制效果。 使用管柱層析及高效能液相層析儀進行純化分離,由上述五味子科植物純化分離出五十八個化合物,包括三十七個18個碳所組成骨架的雙苯[6.8.6]環 (dibenzocyclooctadiene)木質酚素(lignan) 和九個19個碳所組成骨架的高木質酚素(homolignan);四個三萜類;三個固醇類;以及五個芳香環化合物。在山防風之部份,則由其根部分離出十三個主要化合物包含了八個噻吩化合物;四個三萜類;和一個固醇類。這些獲致純化合物中有一個高木質酚素和十個木質酚素係新發現之物質,其新化合物分別為:Schiarisanrins E (23)、Schizanrin F (62)、Schizanrin G (63)、Schizanrin H (64)、Schizanrin I (65)、Schizanrin J (66)、Schizanrin K (67)、Schizanrin L (68)、Schizanrin M (69)、Schizanrin N (70),其化學結構式之鑑定係利用化學方法和各種光譜主要是以1H和13C NMR之二元(2D)技術來解析。 經由抗B型肝炎活性測試,發現四個新發現之18個碳木質酚素和已知(+)-gomisin K3 (33) 木質酚素皆對HBV之表面抗原具有頗強的抑制作用。我們進一步利用已知(一) kadsurarin為起始物接上不同鹵化物和含氮官能基;(二)亦利用(+)-gomisin K3為起始物接上相關苯環或含硫官能基。探討該兩種木質酚素合成衍生物之化學結構和生物活性的關係,結果顯示 (+)-gomisin K3木質酚素接上含硫官能基具有降低毒性和提高抑制B型肝炎病毒表面抗原和e抗原之作用。 在山防風之合成研究方面,利用不具活性的雙硫噻吩化合物5'-(but-3-en-1 -ynyl) -2,2'-bithiophene (1),將其yne-ene結構水解後製備成酮基再接上一系列不同碳鏈的醇基。另外以三硫α-terthienyl (8)為起始物製備成不飽和酮基再接上一系列不同碳鏈的醇基。測試這些噻吩化合物衍生物細胞毒殺後,發現雙硫噻吩衍生物比三硫噻吩衍生物更具抗癌活性。細胞毒殺試驗結果亦顯示雙硫噻吩衍生物碳數不超過三個以上之醇基具有較高的抑制活性作用。 |
Abstract |
bstract Cancer has been the first lethal factor in Taiwan, and hepatitis B is also a serious problem in our country. We have identified that the extracts of Taiwanese Schisandraceous plants, including Schizandra arisanensis, Kadsura matsudai and K. japonica, have inhibitory effect on type B hepatitis surface antigen (HBsAg) and e-antigen (HBeAg). Besides, we also find that the extracts of Echinops grijsii can inhibit the growth of human cancer cell line, KB and Hela. To purify active compounds by using column chromatography and high-performance liquid chromatography, we have furnished fifty-eight compounds from above Schisandraceous plants, including thirty-seven C18 lignans composed of [6.8.6]-dibenzocyclooctadiene skeleton, nine C19 homolignans, four triterpenes, three steroids and five cyclic-aromatic compounds. In the case of Echinops grijsii, we got thirteen major compounds containing eight thiophenes, four triterpenes, and a sterol. Structural elucidation of the novel homolignan and ten lignans are based on the spectral and chemical analyses, mainly by using two-dimensional nuclear magnetic resonance (NMR) of 1H and 13C nucleus. From the anti-HBsAg and anti-HBeAg assay, we found that four of new C18 lignans and one known (+)-gomisin K3 (33) lignan exhibited the significant inhibitory effects on surface antigen of hepatitis B virus. Moreover, to modify the known lignans, kadsurarin with different halogens and functional group having nitrogen atom, as well as (+)-gomisin K3 with several kinds of phenyl compounds and sulfur functional groups are processed. The preliminary structures and bioactivity relationships (SAR) studies demonstrated that (+)-gomisin K3 with sulfuric functional group could decrease cytotoxicity and increase inhibitory effect on surface antigen and e-antigen of hepatitis B virus. In the part of studying synthesis by using inactive 5’-(but-3-en-1-ynyl)-2,2’ -bithiophene (1) from Echinops grijsii, the yne-ene moiety of its structure was hydrolyzed into carbonyl group and then was attached a serious of various carbon number of hydroxy groups. Besides the above experiment, α-trithienyl (1) was served as a substrate and made it into unsaturated carbonyl group, which then was linked with a series of hydroxy groups. Cytotoxicity datum showed that the derivatives of bi-thiophene have better anticancer activity than derivatives of tri-thiophene. And the assay results also exhibited that the bi-thiophene derivatives with hydroxy group with less than three carbon numbers have better inhibitory activity against cancer cells. |
目次 Table of Contents |
目錄 誌謝………………………………………………………………………….i 目錄………………………………………………………………………….ii 圖表目錄…………………………………………………………………….iii 中文摘要……………………………………………………………………...1 英文摘要……………………………………………………………………...2 第一章 緒論………………………………………………………………….4 第一節 前言…………………………………………………………...4 第二節 植物之分佈及型態………………………………………….22 1.漏蘆(山防風)……………………………………………….22 2.小本紅骨蛇…………………………………………………23 3.阿里山五味子………………………………………………24 4.南五味子……………………………………………………25 第三節 研究目的…………………………………………………...26 第二章 實驗分離部份……………………………………………………...27 第一節 山防風、小本紅骨蛇、阿里山五味子和南五味子之 化學成分之抽取與分離流程……………………………...27 1.山防風根部成分之萃取與分離…………………………..27 2.小本紅骨蛇枝葉成分之萃取與分離……………………..29 3.阿里山五味子果實成分之萃取與分離…………………..30 4.南五味子枝葉成分之萃取與分離………………………..31 第二節 植物材料…………………………………………………...39 第三節 實驗儀器與藥品…………………………………………...41 第三章 化合物結構之證明……………………………………………...…43 第一節 Taiwanschirin A (24)之構造證明……………………….....43 第二節 Schiarisanrin A (19)之構造證明…………………………...49 第三節 Schiarisanrin E (23)之構造證明………………………..….55 第四節 Schizanrin F (62)之構造證明……………………………...60 第五節 Schizanrin G (63)之構造證明……………………………..67 第六節 Schizanrin H (64)之構造證明……………………………..74 第七節 Schizanrin I (65)之構造證明……………………………....81 第八節 Schizanrin J (66)之構造證明………………………………88 第九節 Schizanrin K (67)之構造證明……………………………..95 第十節 Schizanrin L (68)之構造證明…………………………….102 第十一節 Schizanrin M (69)之構造證明…………………………109 第十二節 Schizanrin N (70)之構造證明………………………….115 第四章 五味子科植物成分抗B型肝炎及抗癌活性測定……………….121 第五章 木質酚素衍生物之合成………………………………………….129 第一節 Kadsurarin (61)衍生物之合成……………………………129 第二節 (+)-gomisin K3 (33)衍生物之合成……………………....131 第三節 木質酚素衍生物抗B型肝炎活性探討………………....133 第六章 噻吩衍生物之合成…………………………………………….....136 第一節 雙噻吩與天然物活性構想設計………………………….136 第二節 合成具ene-yne官能基雙噻吩化合物88………………..138 第三節 雙噻吩化合物1之水解反應……………………………..141 第四節 噻吩衍生物合成反應…………………………………….143 (一)雙噻吩衍生物合成反應………………………………..143 (二)三噻吩衍生物合成反應………………………………..145 (三)單噻吩衍生物合成反應………………………………..146 第五節 噻吩衍生物抗癌活性討論……………………………….150 第七章 實驗數據部份…………………………………………………….151 第一節 山防風化合物光譜數據………………………………….151 第二節 五味子科植物化合物光譜數據………………………….157 第三節 Kadsurarin (61)和(+)-gomisin K3 (33)衍生物 光譜數據………………………………………………….180 第四節 噻吩衍生物光譜數據…………………………………….188 參考文獻…………………………………………………………………...207 |
參考文獻 References |
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