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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳春雄(Chung-Hsiung Chen),李水盛(Shoei-Sheng Lee) | |
dc.contributor.author | Ching-Ting Lin | en |
dc.contributor.author | 林敬婷 | zh_TW |
dc.date.accessioned | 2021-06-13T00:01:32Z | - |
dc.date.available | 2009-08-08 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-31 | |
dc.identifier.citation | 1.Colombres, M., Sagal, J.P. & Inestrosa, N.C. An overview of the current and novel drugs for Alzheimer's disease with particular reference to anti-cholinesterase compounds. Current Pharmaceutical Design 10, 3123-3132 (2004).
2.Jann, M.W. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy 20, 1-12 (2000). 3.Viegas, C. et al. New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids. Bioorganic & Medicinal Chemistry 13, 4184-4190 (2005). 4.Houghton, P.J., Ren, Y.H. & Howes, M.J. Acetylcholinesterase inhibitors from plants and fungi. Natural Product Reports 23, 181-199 (2006). 5.Park, C.H. et al. Novel anticholinesterase and antiamnesic activities of dehydroevodiamine, a constituent of Evodia rutaecarpa. Planta Medica 62, 405-409 (1996). 6.Cardoso, C.L. et al. Indole glucoalkaloids from Chimarrhis turbinata and their evaluation as antioxidant agents and acetylcholinesterase inhibitors. Journal of Natural Products 67, 1882-1885 (2004). 7.Lopez, S., Bastida, J., Viladomat, F. & Codina, C. Acetylcholinesterase inhibitory activity of some Amaryllidaceae alkaloids and Narcissus extracts. Life Sciences 71, 2521-2529 (2002). 8.Houghton, P.J., Agbedahunsi, J.M. & Adegbulugbe, A. Choline esterase inhibitory properties of alkaloids from two Nigerian Crinum species. Phytochemistry 65, 2893-2896 (2004). 9.Elgorashi, E.E., Stafford, G.I. & van Staden, J. Acetycholinesterase enzyme inhibitory effects of amaryllidaceae alkaloids. Planta Medica 70, 260-262 (2004). 10.Bai, D.L., Tang, X.C. & He, X.C. Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease. Current Medicinal Chemistry 7, 355-374 (2000). 11.Hirasawa, Y., Morita, H., Shiro, M. & Kobayashi, J. Sieboldine A, a novel tetracyclic alkaloid from Lycopoldium sieboldii, inhibiting acetylcholinesterase. Organic Letters 5, 3991-3993 (2003). 12.Rahman, U.A., Atia Tul, W., Nawaz, S.A. & Choudhary, M.I. New cholinesterase inhibiting bisbenzylisoquinoline alkaloids from Cocculus pendulus. Chemical & Pharmaceutical Bulletin 52, 802-806 (2004). 13.Atta Ur, R., Parveen, S., Khalid, A., Farooq, A. & Choudhary, M.I. Acetyl and butyrylcholinesterase-inhibiting triterpenoid alkaloids from Buxus papillosa. Phytochemistry 58, 963-968 (2001). 14.Chiou, C.M., Kang, J.J. & Lee, S.S. Litebamine N-homologues: Preparation and anti-acetylcholinesterase activity. Journal of Natural Products 61, 46-50 (1998). 15.O'Brien, P., Carrasco-Pozo, C. & Speisky, H. Boldine and its antioxidant or health-promoting properties. Chemico-Biological Interactions 159, 1-17 (2006). 16.Jimenez, I. & Speisky, H. Biological disposition of boldine: in vitro and in vivo studies. Phytotherapy Research 14, 254-260 (2000). 17.Lee, S.S., Chiou, C.M., Lin, H.Y. & Chen, C.H. Preparation of Phenanthrene Alkaloids Via Solvolysis of 2-Hydroxyaporphines. Tetrahedron Letters 36, 1531-1532 (1995). 18.Sajiki, H. et al. Pd/C-catalyzed deoxygenation of phenol derivatives using Mg metal and MeOH in the presence of NH4OAc. Organic Letters 8, 987-990 (2006). 19.Mori, A. et al. Mechanistic study of a Pd/C-catalyzed reduction of aryl sulfonates using the Mg-MeOH-NH4OAc system. Chemistry-a European Journal 13, 1432-1441 (2007). 20.Marco-Contelles, J., Carreiras, M.D., Rodriguez, C., Villarroya, M. & Garcia, A.G. Synthesis and pharmacology of galantamine. Chemical Reviews 106, 116-133 (2006). 21.Barker, P., Finke, P. & Thompson, K. Preparation and Cyclization of Aryloxyacetaldehyde Acetals - a General-Synthesis of 2,3-Unsubstituted Benzofurans. Synthetic Communications 19, 257-265 (1989). 22.Ellman, G.L., Courtney, K.D., Andres, V. & Featherstone, R.M. A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity. Biochemical Pharmacology 7, 88-& (1961). 23.Rhee, I.K., van de Meent, M., Ingkaninan, K. & Verpoorte, R. Screening for acetylcholinesterase inhibitors from Amaryllidaceae using silica gel thin-layer chromatography in combination with bioactivity staining. Journal of Chromatography A 915, 217-223 (2001). 24.Michael J. S., Dewar & Tadao Nakaya Oxidative Coupling Phenols. Journal of the American Chemical Society 90, 7134-7135 (1968) 25.Shimizu, K., Tomioka, K., Yamada, S-i. & Koga, K. A biogenetic-type asymmetric synthesis of optically active Amaryllidaceae alkaloids : (+)-and (-)-galanthamine from L-tyrosine. Hetrocycles 8, 277-282 (1977) 26.Szewczyk, J., Lewin, A. H. & Carroll, F. I. An improved synthesis of galanthamine. Journal of Heterocyclic Chemistry 25, 1809-1811 (1988) 27.Szewczyk, J., Wilson, J. W., Lewin, A. H. & Carroll, F. I. Facile synthesis of (±)-, (+)-, and (-)-galanthamine. Journal of Heterocyclic Chemistry 32, 195-199 (1995) 28.Kita, Y., Arisawa, M., Gyoten, M., Nakajima, M., Hamada, R., Toma, H. & Takada, T. Oxidative intramolecular phenolic coupling reaction induced by a hypervalent Iodine(III) reagent : leading to galanthamine-type Amaryllidaceae alkaloids. Journal of Organic Chemistry 63, 6625-6633 (1998) | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28136 | - |
dc.description.abstract | 波爾定鹼(Boldine, 1)為大量存在於杯軸花科(Monimiaceae)、樟科(Lauraceae)或木蘭科(Magnoliaceae)植物中的阿朴芬(aporphine)類生物鹼成分,文獻搜尋可得知其有多種生物活性作用。Litebamine (3)為樟科(Lauraceae)植物山胡椒(Litsea cubeba Persoon)的木部分離出,具有phenanthrene架構的生物鹼,經由生物活性篩選發現其具有抑制乙醯膽鹼酵素之活性。
分析結構發現,boldine (1)與litebamine (3) 結構上氧和氮原子之距離與乙醯膽鹼之乙醯基部份氧原子和膽鹼部分氮原子間相對原子距離類似,故此本論文在於製備這兩類生物鹼衍生物並進一步討論這類化合物之結構與抗乙醯膽鹼酵素活性的關係。 以boldine (1)為起始物,經簡易之半合成方法可大量製備litebamine (3),接著分別在以boldine (1)及litebamine (3)經過酚基保護,催化性氫化反應,及接續之去甲基反應可得到phenanthrene架構去3, 7酚基衍生物(12),此架構於C環飽和之去3, 7酚基衍生物(10, 11),及C和D環皆飽和之衍生物(13, 14);另外也得到aporphine架構去2, 9酚基的衍生物(16, 17, 19, 20)。 以上產物以化合物16對於乙醯膽鹼酵素有較好之抑制活性,其他產物雖活性不高,但仍可用於探討這兩種生物鹼之架構與活性之關係。 | zh_TW |
dc.description.abstract | Boldine (1), an aporphine alkaloid, that is abundantly present in a number of plants of the families including Monimiaceae, Lauraceae and Magnoliaceae. Litebamine (3) is a phenanthrene alkaloid isolated from the wood of Litsea cubeba. It possesses inhibitory activity against acetylcholinesterase (AChE). Comparison of the structure of acetylcholine, boldine (1) and litebamine (3), we can found that the distance between N and O of these three molecules were similar and could act with AChE with similar mode. So the purpose of this thesis was to prepare the boldine (1) and litebamine (3) derivatives for exploration in their SAR with respect to AChE inhibitory activity.
Starting from boldine (1), litebamine (3) was prepared by a facile semisynthetic method. Following subsequently with three reaction steps on 3, protection of the phenolic function with phenyltetrazoyl group, catalytic hydrogenation to remove the phenyltetrazoyloxy group, and demethylation, five products (10-14) were prepared starting from litebamine (3). They are 3,7-didehydroxy-9,10-dihydrolitebamine (10), didehydroxy-O,O-didemethyl-9,10-dihydrolitebamine (11), didehydroxy-O,O-di- demethyllitebamine (12), and didehydroxy-octahydrolitebamine (13, 14). Using boldine (1) as starting materials and via similar approaches, four products (16-17, 19-20) were yielded. They are 1,10-dimethoxyaporphine (16), 1,10-dihydroxyaporphine (17), 1,10-di-diethoxyethoxyaporphine (19), and 1-diethoxyethoxy-10-hydroxyaporphine (20). The bioactivity of these products against acetylcholinesterase has been investigated. The results indicated that compound 16 has better inhibitory activity against AChE. The result, however, provide further informations regarding SAR of these two kinds of alkaloids. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:01:32Z (GMT). No. of bitstreams: 1 ntu-96-R94423015-1.pdf: 5335106 bytes, checksum: 80403f5561bf55bd6d93921b8f18145c (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 壹、 序論及研究目的...................................1
1.1 阿茲海默症之治療與乙醯膽鹼酵素抑制劑之關係...........1 1.2 已核准上市的乙醯膽鹼酵素抑制劑.......................1 1.3 乙醯膽鹼酵素之結構與催化機轉.........................2 1.4 近年來研究發現其他具有AChE抑制活性之生物鹼成分.......4 1.5 研究目的.............................................8 1.6 Boldine衍生物之活性研究..............................9 1.7 Litebamine衍生物之活性研究..........................10 貳、實驗結果與討論 .......................................11 2.1 Litebamine (3)之大量製備 ...........................11 2.2 Litebamine衍生物(9)-(12) 的製備.....................14 2.3 1, 10-Dihydroxyaporphine (17)之製備.................24 2.4 1-Diethoxyethoxy-10-hydroxyaporphine (20)之製備.....25 2.5 Boldine及litebamine衍生物之生物活性研究.............33 2.5.1 抑制乙醯膽鹼酵素(AChE)之活性測試結果...............33 2.5.2 活性測試結論 .......................................34 參、實驗材料與方法 .......................................35 3.1 儀器與器材..........................................35 3.1.1 理化性質測定儀器..................................35 3.1.2 反應器............................................35 3.1.3 成份分離之儀器及材料..............................35 3.1.4 試劑、材料及溶劑..................................36 3.2 Litebamine衍生物的製備 ..............................37 3.2.1 Secoboldine (2)之製備14...........................37 3.2.2 Litebamine (3)之製備14............................38 3.2.3 8, 8’-Methylenebislitebamine (8)之製備...........38 3.2.4 3,7-O,O-Diphenyltetrazoyl-litebamine (9)之製備....39 3.2.5 3,7-Didehydroxy-9,10-dihydrolitebamine (10)之製備.40 3.2.6 3,7-Didehydroxy-4,6-O,O-didemethyl-9,10-dihydrolitebamine (11) 及3,7-Didehydroxy-4,6-O,O-didemethyllitebamine (12)之製備..........................41 3.2.7 (4b, 8a)-cis, (4b, 6)-trans-3,7-Didehydroxy-(4b-10)-octahydrolitebamine(13)及(4b, 8a)-cis -3,7-Didehydroxy-6-demethoxy-(4b-10)-octahydrolitebamine (14)之製備.......42 3.3 Boldine衍生物的製備.................................44 3.3.1 2,9- O,O-Diphenyltetrazoyl-boldine (15)之製備.....44 3.3.2 1,10-Dimethoxyaporphine (16)之製備................45 3.3.3 1,10-Dihydroxyaporphine.hydrobromide (17)之製備..46 3.3.4 10-t-Butyldimethylsilyloxy-1-hydroxyaporphine (18)之製備.....................................................47 3.3.5 1,10-Di-diethoxyethoxyaporphine (19)之製備........47 3.3.6 1-Diethoxyethoxy-10-hydroxyaporphine (20)之製備...48 3.3.7 產物A之試製.......................................49 3.3.7.1 方法I 24, 25.....................................49 3.3.8 產物B之試製 .......................................50 3.3.9 產物C之試製 21....................................50 3.4 Boldine及litebamine衍生物之生物活性研究.............51 3.4.1 抗乙醯膽鹼酵素活性試驗(Acetylcholinesterase inhibition assay)所用試劑與儀器..........................51 3.4.2 抗乙醯膽鹼酵素活性試驗(Acetylcholinesterase inhibition assay)........................................51 3.4.2.1 原理.............................................51 3.4.2.2 實驗方法:.......................................52 參考文獻.................................................55 附圖(Spectra Appendices).................................58 | |
dc.language.iso | zh-TW | |
dc.title | Boldine及Litebamine衍生物之製備與生物活性研究 | zh_TW |
dc.title | Preparation and Bioactivity Study of Boldine and Litebamine Derivatives | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳繼明,李安榮 | |
dc.subject.keyword | 波爾定鹼,阿朴芬類生物鹼,litebamine,phenanthrene型生物鹼,乙醯膽鹼酵素,乙醯膽鹼酵素抑制活性, | zh_TW |
dc.subject.keyword | boldine,aporphine alkaloid,litebamine,phenanthrene alkaloid,acetylcholinesterase,acetylcholinesterase inhibitory activity, | en |
dc.relation.page | 109 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-31 | |
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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