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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李水盛(Shoei-Sheng Lee) | |
dc.contributor.author | Sheng-Fa Tsai | en |
dc.contributor.author | 蔡勝發 | zh_TW |
dc.date.accessioned | 2021-06-15T06:54:57Z | - |
dc.date.available | 2014-03-03 | |
dc.date.copyright | 2011-03-03 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-02-10 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48390 | - |
dc.description.abstract | 第一部分:利用高效液相層析-活性篩選技術研究圓滑番荔枝抗乙醯膽鹼酯酶成分
在阿茲海默症的治療上,乙醯膽鹼酯酶抑制劑證實為延緩惡化的藥物,目前只有少數這類藥物被FDA 核准,為充實其藥源及降低副作用,仍有開拓的必要。故本研究擬利用高效液相層析微量分離法連結活性分析系統,加速發現與分離具有抗乙醯膽鹼酯酶之天然物活性成分,以期尋找治療阿茲海默症之先導藥物。 本實驗先依一般生物鹼之抽取方法進行圓滑番荔枝(Annona glabra L.)莖部乙醇抽取物之成分劃分,再以活性導向進行分離。在初步篩選抗乙醯膽鹼酯酶活性試驗中,發現酸性氯仿層的活性次組分具有較高活性,進一步將活性次組分利用高效液相層析微量分離法連結活性分析系統進行分離,先將分析級規模樣品以高效液相層析分離於96微孔盤,經離心真空濃縮後進行活性試驗,具活性部分再次利用半製備高效液相層析進行分離,再鑑定活性成分結構及作用強度。以此方法總共分離出20個活性化合物,經由光譜、質譜分析這些化合物的結構,其中有四個新化合物,即三個原小蘗鹼類(protoberberines)- (7S,14S)-10-O-demethylxylopinine N-metho salt (3)、S-(-)-7,8-didehydro-10-O-demethylxylopininium salt (10)、S-(-)-7,8-didehydrocorydalminium salt (11)及一個1-azaanthraquinone類化合物5-methoxymarcanine A (17),化合物10及11並為首見的含7,8-雙去氫的原小蘗鹼類天然物。化合物3、pseudocolumbamine (12)、palmatine (15) 及pseudopalmatine (16) 具有較高的抗乙醯膽鹼酯酶活性,其IC50分別為8.4、5.0、0.4及1.8 μM。 第二部分:十四種樟科木薑子及新木薑子屬之黃酮類成分研究 本研究的目的為利用高效液相層析串聯固相萃取及核磁共振和液相層析/質譜串聯技術分析台灣木薑子及新木薑子屬的黃酮類成分的化學多樣性。自長葉木薑子(L. acuminate)、大葉屏東木薑子(L. akoensis var. Chitouchiaoensis)、小梗木薑子( L. krukovii)、高山新木薑子(N. acuminatissima)及五掌楠(N. konishii)葉部共鑑定出14個黃酮類化合物,其中quercetin 3-O-(2-O-β-D-apiofuranosyl)-α-L-rhamnoside為新化合物,依據上述資料以HPLC建立十四個植物葉部的黃酮類化合物組成及含量數據,其中高山新木薑子葉部含有最多量的黃酮類成分 (ca. 0.24%, w/w)。 故利用高效液相層析串聯固相萃取及核磁共振和液相層析/質譜聯用技術有效加速天然物化學成分的分析,最大優勢為用分析級規模的樣品即能快速確認天然物中的化合物結構。 第三部分:ALZ-1改善大鼠記憶之研究 基於阿茲海默症的病因可能與膽鹼路徑(cholinergic system)之活性有關,而先前研究發現在體外試驗中天然物ALZ-1可抑制乙醯膽鹼酯酶活性,故本研究進一步以失智症動物模型驗證ALZ-1對於學習記憶的促進作用。利用不同的學習記憶模式,以主動迴避學習試驗及莫氏水迷宮試驗皆發現,口服給予ALZ-1 (1及10 mg/kg, p.o.),阻止了東莨菪鹼(scopolamine, 1 mg/kg, i. p.)所引起的學習缺陷,在莫氏水迷宮試驗證實可以縮短逃避時間,在主動迴避學習試驗發現可以增加逃避成功率,皆明顯促進大白鼠在學習記憶試驗上的表現,因此ALZ-1對於改善阿茲海默症所引起的記憶缺陷有進一步發展的潛力。 | zh_TW |
dc.description.abstract | Part 1 Characterization of acetylcholinesterase inhibitory constituents from Annona glabra assisted by HPLC micro-fractionation
Acetylcholinesterase (AChE) inhibitors are used as an effective approach to treat Alzheimer’s disease (AD). Up to now, only a few AChE inhibitors have been approved for such purpose due to the side effects. Thus, the search for safer and effective AChE inhibitors is still a demand for the treatment of AD. Since natural products are versatile and often serve as drug lead for further development, a simple assay system was applied to explore the potential AChE inhibitors from higher plants. The EtOH extract of the stem of Annona glabra L. (Annonaceae) was found to be active against AChE. Thus the characterization of the anti-AChE constituents from this plant extract was the aim of this study. The active fraction was analyzed by combining HPLC micro-fractionation with a bioassay. The analytical-scale sample was fractionated by HPLC-DAD into 96-well microplates, which, after condentration using centrifugal vacuum evaporator, were assayed against AChE. The active subfractions were separated over semi-preparative HPLC to give twenty compounds. Four of these, (7S,14S)-10-O-demethylxylopinine N-metho salt (3), S-(-)-7,8-didehydro-10-O-demethylxylopininium salt (10), S-(-)-7,8-didehydrocorydalminium salt (11), and 5-methoxymarcanine A (17), were assigned as new natural products. In addition, compounds 10 and 11 represent the first natural occurrence of 7,8-didehydroprotoberberines. Compound 3, pseudocolumbamine (12), palmatine (15), and pseudopalmatine (16) showed anti-AChE IC50 values of 8.4, 5.0, 0.4 and 1.8 μM, respectively. Part 2 Flavonoid composition in the leaves of 14 Neolitsea and Litsea plants This study was aimed to study the chemodiversity of flavonoids in the Formosan Litsea and Neolitsea plants. Applications of LC-SPE-NMR and LC/MS hyphenated techniques in analyzing polar constituents from the leaves of L. acuminata, L. akoensis var. Chitouchiaoensis, L. krukovii, N. acuminatissima, and N. konishi led to the identification of 13 known flavonoids and one new flavonol dioside, quercetin 3-O-(2-O-β-D-apiofuranosyl)-α-L-rhamnopyranoside. The quantity and variety of flavonoid composition in the leaves of 14 Litsea and Neolitsea plants were examined to enable more effective utilization of such bioactive ingredients. Of these, N. acuminatissima was found to contain the most quantity of flavonoids (ca. 0.24%, w/w, leaves). Part 3 ALZ-1 attenuates scopolamine-induced amnesia in rats The deficiency in cholinergic neurotransmitter is an important feature of Alzheimer's disease (AD). Acetylcholinesterase (AChE) inhibitor is one of the rational therapeutic targets to improve AD. From in vitro study, IC50 of ALZ-1 for AChE inhibitory activity is 1.56 uM. The effects of ALZ-1 on the scopolamine-induced memory deficits in rats were examined in Morris water maze and active shuttle avoidance. Scopolamine (1 mg/kg, i.p.), the antagonist of cholinergic receptors, caused significant impairments on a wide range of learning and memory tasks. We investigated the effects of ALZ-1 on memory disturbances induced by scopolamine, since ALZ-1 (1 and 10 mg/kg, p.o.) had greater efficacy than scopolamine group on the improvement of scopolamine-induced learning and memory errors, respectively. These in vivo findings by two behavioural paradigms suggest ALZ-1, as a therapeutic potential of orally active AChE inhibitor, for improving learning and memory in AD. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T06:54:57Z (GMT). No. of bitstreams: 1 ntu-100-D93423003-1.pdf: 7376277 bytes, checksum: 00be36c116ae242c08b1f35295e38156 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 口試委員會審定書………………………………………………………I
誌謝………………………………………………………………………II 中文摘要………………………………………………………………III 英文摘要…………………………………………………………………V 目錄……………………………………………………………………VII 表目錄……………………………………………………………………IX 圖目錄……………………………………………………………………X 流程圖目錄………………………………………………………………XI 辭彙縮寫…………………………………………………………………XI 第一部分:利用高效液相層析-活性篩選技術研究圓滑番荔枝抗乙醯膽鹼酯酶成分…1 第一章 緒論……………………………………………………………1 1.1研究目的………………………………………………………………1 1.2阿茲海默症及臨床治療用藥…………………………………………1 1.2.1阿茲海默症之盛行率………………………………………………1 1.2.2阿茲海默症之成因…………………………………………………2 1.2.3阿茲海默症之治療用藥……………………………………………2 1.2.4乙醯膽鹼酯酶抑制劑的作用機轉…………………………………3 1.3高效液相層析微量分離法連結活性分析系統………………………4 1.4 圓滑番荔枝Annona glabra L之簡介………………………………5 1.4.1 圓滑番荔枝之生物鹼成分………………………………………6 第二章 實驗結果與討論………………………………………………17 2.1圓滑番荔枝莖部成分之分離………………………………………17 2.2高效液相層析微量分離法連結活性分析…………………………17 2.2.1新天然化合物3、10、11、17之結構鑑定………………………21 2.2.2已知化合物1-2、4-9、12-16、18-20之結構鑑定……………26 2.3 抑制乙醯膽鹼酯酶(AChE)之活性測試結果………………………31 2.4 討論…………………………………………………………………33 2.5 結論…………………………………………………………………34 第三章 實驗方法………………………………………………………35 3.1 儀器與材料…………………………………………………………35 3.2圓滑番荔枝莖部成分之萃取與分離………………………………36 3.3分析級高效液相層析微量分離法連結抗乙醯膽鹼酯酶活性分析系統…37 3.4 生物活性研究………………………………………………………37 3.5以半製備型管柱分離化合物1-20 …………………………………39 3.6各化合物之物理數據………………………………………………40 第二部分:十四種樟科木薑子及新木薑子屬之黃酮類成分研究……46 第一章 緒論……………………………………………………………46 1.1研究目的……………………………………………………………46 1.2木薑子屬及新木薑子屬植物介紹…………………………………46 1.2.1木薑子屬形態特徵………………………………………………46 1.2.2新木薑子屬形態特徵……………………………………………47 1.3 黃酮類………………………………………………………………48 1.3.1木薑子及新木薑子屬的黃酮類成分…………………………48 1.4 LC-SPE-NMR Hyphenation之簡介…………………………………51 第二章 實驗結果與討論………………………………………………53 2.1 14種植物葉部成分分離……………………………………………53 2.2 黃酮類化合物鑑定…………………………………………………54 2.2.1化合物25、29分離及鑑定………………………………………65 2.3 Rutin、isoquercitrin、quercetin 3-O-α-rhamnopyranoside 及 kaempferol 3-O-α-rhamnopyranoside的定量…………………68 2.4結論…………………………………………………………………71 第三章 實驗方法………………………………………………………72 3.1 儀器與材料…………………………………………………………72 3.2 14種木薑子屬及新木薑子屬植物葉部成分之抽取與分離……74 3.3 HPLC-SPE-NMR和LC-MS之分析………………………………74 3.4 以半製備型管柱分離化合物25 及29……………………………75 3.5 化合物25及 29之物理數據………………………………………75 3.6 Rutin、isoquercitrin、quercetin 3-O-α-rhamnopyranoside 及 kaempferol 3-O-α-rhamnopyranoside的定量…………………76 第三部分:ALZ-1改善大鼠記憶之研究………………………………77 第一章 緒論…………………………………………………………77 1.1研究目的……………………………………………………………77 1.2阿茲海默症…………………………………………………………77 1.3東莨菪鹼誘發學習記憶障礙-失智症動物模型……………………78 1.4記憶學習能力行為測試……………………………………………78 1.4.1 Morris 水迷宮行為測試………………………………………78 1.4.2主動迴避學習……………………………………………………79 1.5 ALZ-1………………………………………………………………81 第二章 實驗結果與討論………………………………………………82 2.1主動迴避試驗………………………………………………………82 2.2 水迷宮試驗…………………………………………………………84 2.3. 討論………………………………………………………………85 第三章 實驗方法………………………………………………………86 3.1 儀器與材料………………………………………………………86 3.2 實驗動物……………………………………………………………86 3.3試驗物質配製………………………………………………………86 3.4給藥模式……………………………………………………………86 3.5實驗分組……………………………………………………………86 3.6評估試驗……………………………………………………………87 3.6.1主動迴避試驗……………………………………………………87 3.6.2 水迷宮試驗………………………………………………………87 3.7 統計方法……………………………………………………………88 參考文獻…………………………………………………………………89 附圖………………………………………………………………………97 | |
dc.language.iso | zh-TW | |
dc.title | 第一部分:利用高效液相層析-活性篩選技術研究圓滑番荔枝抗乙醯膽鹼酯酶成分;第二部分:十四種樟科木薑子及新木薑子屬之黃酮類成分研究;第三部分:ALZ-1改善大鼠記憶之研究 | zh_TW |
dc.title | Part 1:Characterization of acetylcholinesterase inhibitory constituents from Annona glabra assisted by HPLC micro-fractionation;Part 2:Flavonoid composition in the leaves of 14 Neolitsea and Litsea plants;Part 3:ALZ-1 attenuates scopolamine-induced amnesia in rats | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳春雄,陳繼明,李安榮,林雲蓮,郭錦樺 | |
dc.subject.keyword | 乙醯膽鹼酯酶,圓滑番荔枝,高效液相層析-活性篩選技術,小蘗鹼,木薑子屬,新木薑子屬,黃酮類,高效液相層析串聯固相萃取及核磁共振串聯技術,阿茲海默症,東莨菪鹼,水迷宮試驗,主動迴避學習試驗, | zh_TW |
dc.subject.keyword | Acetylcholinesterase inhibitor,Annona glabra,HPLC Micro-fractionation,berberine,Litsea,Neolitsea,flavonoid glycosides,HPLC-SPE-NMR,LC-MS,scopolamine,Morris water maze,active shuttle avoidance, | en |
dc.relation.page | 161 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-02-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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