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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78690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 | Yu-Ping Jiang | en |
| dc.contributor.author | 江宇評 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:12:28Z | - |
| dc.date.available | 2022-08-28 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-03 | |
| dc.identifier.citation | 1. Holly Kramer, Gary Curhan. The association between gout and nephrolithiasis: the national health and nutrition examination survey III, 1988-1994. American Journal of Kidney Diseases 2002, 40, 37–42.
2. Chang-Fu Kuo, Matthew Grainge, Weiya Zhang, Michael Doherty. Global epidemiology of gout: prevalence, incidence and risk factors. Nature Reviews Rheumatology 2015, 11, 649–662. 3. Ayelen Ramallo, Susana Zacchino, Ricardo Furlan. A rapid TLC autographic method for the detection of xanthine oxidase inhibitors and superoxide scavengers. Phytochemical Analysis 2006, 17, 15–9. 4. Yuji Moriwaki, T Mitsui Petrochemica Yamamoto, Jun-ichi Yamakita, Sumio Takahashi, et al. Zonal distribution of allopurinol-oxidizing enzymes in rat liver. Advances in Experimental Medicine and Biology 1998, 431, 47–50. 5. Jin Kyu Kim, Woo Jung Kim, Jung Mi Hyun, Jong Suk Lee, et al. Salvia plebeia extract inhibits xanthine oxidase activity in vitro and reduces serum uric acid in an animal model of hyperuricemia. Planta Medica 2017, 83, 1335–1341. 6. Anne-Kathrin Tausche, Rieke Alten, Nicola Dalbeth, Jeff Kopicko, et al. Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study. Rheumatology 2017, 56, 2170–2178. 7. Tomonori Unno, Akio Sugimoto, Takami Kakuda. Xanthine oxidase inhibitors from the leaves of Lagerstroemia speciosa (L.) Pers. Journal of Ethnopharmacology 2004, 93, 391–395. 8. Bhc Khoo, Yung Hian Leow. A review of inpatients with adverse drug reactions to allopurinol. Singapore Medical Journal 2000, 41, 156–60. 9. John Pittman, Michael Bross. Diagnosis and management of gout. American Family Physician 1999, 59, 1799–806. 10. Amy Cannella, Ted Mikuls. Understanding treatments for gout. The American Journal of Managed Care 2005, 11, 451–458. 11. Raj Kumar, Darpan, Sahil Sharma, Rajveer Singh. Xanthine oxidase inhibitors: a patent survey. Expert Opinion on Therapeutic Patents 2011, 21, 1071–108. 12. Cristofer Enroth, Bryan Eger, Ken Okamoto, Tomoko Nishinoi, et al. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. Proceedings of the National Academy of Sciences 2000, 97, 10723–10728. 13. Neelam Malik, Priyanka Dhiman, Anurag Khatkar. In silico design and synthesis of hesperitin derivatives as new xanthine oxidase inhibitors. BMC Chemistry 2019, 13, 53. 14. Sheng-Fa Tsai, Shoei-Sheng Lee. Neolignans as xanthine oxidase inhibitors from Hyptis rhomboids. Phytochemistry 2014, 101, 121–127. 15. Peter O’Brien, Catalina Carrasco-Pozo, Hern ́an Speisky. Boldine and its antioxidant or health-promoting properties. Chemico-Biological Interactions 2006, 159, 1–17. 16. Inés Jiménez, Hernán Speisky. Biological disposition of Boldine: in vitro and in vivo studies. Phytotherapy Research 2000, 14, 254–260. 17. 沈佳錚，Laurolitsine之化學分離法研究，國立台灣大學醫學院藥學研究所碩士論文，1999。 18. Shoei-Sheng Lee, Chi-Ming Chiou, Huey-Yi Lin, Chung-Hsiung Chen. Preparation of phenanthrene alkaloids via solvolysis of 2-hydroxyaporphines. Tetrahedron Letters 1995, 36, 1531–1532. 19. Kovuru Gopalaiah, Anupama Saini, Sankala Chandrudu, Devarapalli Rao, et al. Copper-catalyzed aerobic oxidative coupling of o-phenylenediamines with 2-aryl/heteroaryl ethylamines: direct access to construct quinoxalines. Organic & Biomolecular Chemistry 2017, 15, 2259–2268. 20. 林敬婷，Boldine及Litebamine衍生物之製備與生物活性研究，國立台灣大學醫學院藥學研究所碩士論文，2007。 21. 邱繼明，Litebamine, Thaliporphine及Caryachine衍生物之製備與生物活性研究，國立台灣大學醫學院藥學研究所博士論文，1997。 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78690 | - |
| dc.description.abstract | Boldine為具有Aporphine架構之生物鹼，主要分離自杯軸花科(Monimiaceae)植物波多樹(Boldo, Peumus boldus Molina)之葉與樹皮。Laurolitsine亦為具有Aporphine架構之新型生物鹼，其主要由樟科(Lauraceae)植物台灣雅楠(Phoebe formosana)之莖部分離出來。根據文獻資料可得知此兩化合物均具有多種生物活性作用。
首先，根據電腦分子模擬分析發現：對於黃嘌呤氧化酶(xanthine oxidase)，Aporphine與Secoaporphine呈現良好的對接(嵌合)結果。然而，在實際的體外活性測試結果中，此類化合物對於黃嘌呤氧化酶的抑制效果卻不如預期。原因可能為Aporphine中的氮原子會自動質子化，造成Aporphine變成游離鹼(free base)而帶有正電荷，使得在電腦分子模擬的對接(嵌合)系統中會增加額外的離子交互作用。然而，在生物體或藥理活性測試中的酸鹼值大約在pH 7.5，Aporphine在此環境下由於酸性不足以使氮原子質子化，故在電腦分子模擬與體外活性測試中之結果產生出入。為了驗證此推論，本論文合成具有四級胺或三級胺之Aporphine與Secoaporphine，並進行體外的活性測試加以證實。 以Boldine (1)作為起始物，先進行N-methylation，加熱時溫度的高低會產生不同的化合物。於常溫，產生N-Methylated quaternary ammonium salt；於高溫，則產生開環的N-Methylsecoboldine (5)。然而，直接常溫下進行N-methylation產生N-Methylboldinium halide (4)之產率小於30%，故改為先將Boldine (1)經由乙醯基保護再進行N-methylation，最後以酸水解反應切掉乙醯基，即可得到較高產率之N-Methylboldinium halide (4)。另外，亦將N-Methylsecoboldine (5)先經過乙醯化取得N-Methyldiacetylsecoboldine (6)後，再進行N-methylation與酸水解反應，得到N,N-Dimethylsecoboldinium chloride (7)。 此外，亦透過電腦分子模擬設計與分析其他Aporphine之相關結構，以期許發現其他具有抑制黃嘌呤氧化酶之成分。此部分之主要來源為修飾過去於O-methylation製備Glaucine時所得到反應不完全的Monomethyl Derivatives of Boldine以及透過半合成之方式將對接(docking)結果優良之化學結構製備出來，並進一步探討這類化合物與黃嘌呤氧化酶之活性關係。 在修飾Monomethyl Derivatives of Boldine的部分，以N-Methyllauroletenine (A)與Predicentrine (B)之混合物為起始物。由於兩者之物理特性相近，難以分離純化，故由先前發現之2-Hydroxyaporphine可藉由溶劑熱解反應(Solvolysis reaction)將Predicentrine (B)進行開環，得到Secopredicentrine (8)。此時，混合物N-Methyllauroletenine (A)與Predicentrine (B)之極性差異變大，因此便可將Secopredicentrine (8)分離純化，並進一步將Secopredicentrine (8)進行環化，得到2a-Methyl-7-O-methyllitebamine (9)。再者，亦透過電腦分子模擬設計出兩種系列具有三個苯環及一個六圓環之化學結構，兩系列主要差異於：系列一為環化之二級胺，系列二則為環化之三級胺，即其氮原子上帶有一個甲基。系列一以原油的Laurolitsine作為起始物，經簡易半合成方法可大量製備N-Acetyllaurolitsine (10)，接著進行開環與水解反應。然而，根據不同的反應條件，可得到開環但未水解之N-Acetylsecolaurolitsine (11)與開環且水解之Secolaurolitsine (12)。接著，將Secolaurolitsine (12)進行曼尼希反應(Mannich reaction)，即可得到環化之Norlitebamine (13)。系列二則再次以Boldine (1)作為起始物，經簡易半合成方法可大量製備Secoboldine (14)，並同樣進行曼尼希反應(Mannich reaction)以得到相關之環化衍生物 (15, 16)。 在活性測試結果中，可證實第一部分之氮原子的自動質子化會造成電腦計算與實際藥理活性測試的結果產生出入。於第二部分與第三部分所製備出的化合物亦進行活性的探討。整體而言，可知N-Dimethylsecoboldinium chloride (7)具有最佳的抑制能力，而N-Methylsecoboldine (5)、2a-Methyl-7-O-methyllitebamine (9)、Norlitebamine (13)、2a-Methyllitebamine (15)以及2a-Ethyllitebamine (16)亦具有一定的抑制效果。以上七種化合物對於黃嘌呤氧化酶的抑制效果雖然不盡相同，仍期許未來這些化合物能有助於Aporphine類之高尿酸血症或痛風用藥之開發。 | zh_TW |
| dc.description.abstract | Boldine is an alkaloid with skeleton of Aporphine. It is mainly separated from leaves and barks of Boldo, Peumus boldus Molina which belongs to Monimiaceae family. Laurolitsine is also a new alkaloid with skeleton of Aporphine. And it is mainly separated from stems of Phoebe formosana which belongs to Lauraceae family. According to literature, there are many kinds of biological activities in these two alkaloids.
First, according to the computer molecular modeling analysis, Aporphine and Secoaporphine demonstrate high docking scores on xanthine oxidase, even much better than Febuxostat which is the clinically used drug nowadays. Nevertheless, some kinds of Aporphines and Secoaporphines displayed only medium inhibitory activities in vitro assay. The reason might be attributed to the auto-protonation of N-containing Aporphines and Secoaporphines in docking system. The condition makes the free base Aporphines positive charged and arising else ionic interaction. So that there were different results between in vitro assay and computer molecular modeling. To confirm the hypothesis above, Aporphines and Secoaporphines with quaternary or tertiary amines have been semisynthesized in this thesis. The starting material Boldine (1) was converted to N-methylation. The temperature played a key role in this condition. In room temperature, The N-methylated quaternary ammonium salt was prepared; however, it produced N-Methylsecoboldine (5) in high temperature. Still, the yield of N-Methylboldinium halide (4) was less than 30% in this method. Following subsequently with three reaction steps on Boldine (1), protection with the acetyl group, N-methylation and hydrolysis, the N-Methylated quaternary ammonium salt was prepared in higher yield. Moreover, N-Methylsecoboldine (5) was also converted to acetylation, N-methylation and hydrolysis, and N,N-Dimethylsecoboldinium salt (7) was prepared. Besides, hoping to find another structures that are also able to inhibit xanthine oxidase, there are some relative structures to Aporphine are designed and analyzed by computer molecular modeling analysis. These parts are to modify the Monomethyl Derivatives of Boldine from past work and to semisynthesize the compounds with good docking scores. In modification of Monomethyl Derivatives of Boldine, it is starting from the mixture of N-Methyllauroletenine (A) and Predicentrine (B). Owing to the similar physical characteristics, these two compounds are separated with difficulty. Thus, to get ring-opening Secopredicentrine (8) from Predicentrine (B) by Solvolysis reaction of 2-Hydroxyaporphine. The polarities are different from N-Methyllauroletenine (A) and Secopredicentrine (8). Then, Secopredicentrine (8) can be separated easily from the mixture and also form 2a-Methyl-7-O-methyllitebamine (9) by cyclization. Moreover, there are two series compounds with three benzene rings and a six-membered ring by computer molecular modeling design and analysis. Series-1 is secondary amine, and Series-2 is tertiary amine. In Series-1, starting from crude Laurolitsine, N-Acetyllaurolitsine (10) was prepared by a facile semisynthetic method. According to different conditions, N-Acetylsecolaurolitsine (11) and Secolaurolitsine (12) were prepared. Then, Secolaurolitsine (12) formed Norlitebamine (13) via Mannich reaction. In Series-2, starting from Boldine (1) again, Secoboldine (14) was prepared by a facile semisynthetic method. Then, Secoboldine (14) formed relative derivatives (15, 16) via Mannich reaction as well. In the result of bioassay, it is provable that the auto-protonation of N-containing Aporphine makes the result of computer molecular modeling different from the result of in vitro assay in part one. And the compounds prepared in part two and part three also do the bioassay of xanthine oxidase. In general, N-Dimethylsecoboldinium chloride (7) is with the best inhibition against xanthine oxidase. And N-Methylsecoboldine (5), 2a-Methyl-7-O-methyllitebamine (9), Norlitebamine (13), 2a-Methyllitebamine (15) and 2a-Ethyllitebamine (16) are with not bad inhibition against xanthine oxidase as well. These results will serve as a vital index for developing potential drugs of the Aporphine type for helping treat hyperuricemia or gout. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:12:28Z (GMT). No. of bitstreams: 1 ntu-108-R06423006-1.pdf: 6385681 bytes, checksum: 50bb0eaa4eed899d9d69995e29a7a4fe (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 總目錄
中文摘要 I 總目錄 VI 表目錄(List of Tables) IX 流程圖目錄(List of Schemes) IX 圖目錄(List of Figures) XI 辭彙(Glossary) XVI 目錄 壹、緒論及研究目的 1 1.1 痛風與高尿酸血症之治療與黃嘌呤氧化酶抑制劑的關係 1 1.2 已核准上市的黃嘌呤氧化酶抑制劑 2 1.3 黃嘌呤氧化酶之結構與催化機轉 4 1.4 近年來研究發現其他具有xanthine oxidase抑制活性之天然物成分 5 1.5 研究目的 10 1.6 設計其他的Aporphine相關結構及其電腦計算之自由結合能(∆G) 12 1.7 Boldine衍生物之活性研究 13 1.8 Laurolitsine衍生物之活性研究 14 貳、實驗結果與討論 15 2.1 N-Methylboldinium halide (4)之製備 15 2.2 N-Methylsecoboldine (5)之製備 18 2.3 N-Dimethylsecoboldinium chloride (7)之製備 20 2.4 Secopredicentrine (8)與2a-Methyl-7-O-methyllitebamine (9)之製備 22 2.5 N-Acetyllaurolitsine (10)之大量製備 24 2.6 Secolaurolitsine (12)與N-Acetylsecolaurolitsine (11)之製備 25 2.7 Model Study 26 2.8 系列一(具有二級胺之環化結構)衍生物之製備 29 2.8.1 Norlitebamine (13)之製備 29 2.9 Secoboldine (14)之大量製備 32 2.10 系列二(具有三級胺之環化結構)衍生物之製備 33 2.11 Boldine與Laurolitsine衍生物之抑制黃嘌呤氧化酶活性之研究 35 2.11.1 體外黃嘌呤氧化酶(xanthine oxidase)之活性測試結果 35 2.12 總結 36 3.1 儀器與材料 37 3.1.1 理化性質測定儀器 37 3.1.2 反應器 37 3.1.3 成分分離之儀器及材料 37 3.2 Boldine與Laurolitsine衍生物的製備 40 3.2.1 Diacetylboldine (2)之製備 40 3.2.2 N-Methyldiacetylboldinium iodide (3)之製備 42 3.2.3 N-Methylboldinium halide (4)之製備 44 3.2.4 N-Methylsecoboldine (5)之製備 46 3.2.5 N-Methyldiacetylsecoboldine (6)之製備 48 3.2.6 N-Dimethylsecoboldinium chloride (7)之製備 49 3.2.7 Secopredicentrine (8)之製備 51 3.2.8 2a-Methyl-7-O-methyllitebamine (9)之製備 53 3.2.9 N-Acetyllaurolitsine (10)之製備 55 3.2.10 N-Acetylsecolaurolitsine (11)之製備 57 3.2.11 Secolaurolitsine (12)之製備 59 3.2.12 Norlitebamine (13)之製備 61 3.2.13 Secoboldine (14)之製備 63 3.2.14 2a-Methyllitebamine (15)之製備 65 3.2.15 2a-Ethyllitebamine (16)之製備 67 3.3 Boldine與Laurolitsine衍生物之抑制黃嘌呤氧化酶活性之研究 69 3.3.1 抑制黃嘌呤氧化酶活性試驗(xanthine oxidase inhibition assay)所用試劑與儀器 69 3.3.2 抑制黃嘌呤氧化酶活性試驗(xanthine oxidase inhibition assay) 69 3.3.2.1 原理 69 3.3.2.2 實驗方法 69 參考文獻 72 附圖 (Spectra Appendices) 74 表目錄(List of Tables) Table 1. 痛風治療藥物之種類與介紹 2 Table 2. 化合物Ⅰ–ⅩⅢ對於xanthine oxidase的抑制活性(IC50)與∆G (binding affinity) 7 Table 3. 異喹啉類之結合親和力(binding affinity)數值 8 Table 4. Aporphine衍生物對於xanthine oxidase的抑制率與∆G (binding affinity) 10 Table 5. 新設計化合物之結構與配位值 13 Table 6. N-Acetyllaurolitsine (10)之氫譜結果與文獻(Ref. 21)之比較 24 Table 7. Model Study之實驗條件與結果(Step 1) 27 Table 8. Model Study之實驗條件與結果(Step 2) 28 Table 9. Secolaurolitsine (12)與Norlitebamine (13)之溶解度測試表 29 Table 10. 系列一衍生物2a-Methylnorlitebamine (G) (R = Me)之實驗結果 30 Table 11. Secoboldine (14)之氫譜結果與文獻(Ref. 20)之比較 32 流程圖目錄(List of Schemes) Scheme 1. Preparation of N-Methylboldinium halide (4) from Boldine (1) via 2 methods 16 Scheme 2. Mechanism of the methylation from Boldine (1) to N-Methylboldinium halide (4) 16 Scheme 3. Mechanism of the acetylation from Boldine (1) to Diacetylboldine (2) 17 Scheme 4. Mechanism of N-methylation, then hydrolysis from Diacetylboldine (2) to N-Methylboldinium halide (4) 17 Scheme 5. Preparation of Boldine N-Metho salt from Boldine (1) to N-Methylboldinium halide (4) or N-Methylsecoboldine (5) 18 Scheme 6. Mechanism of the ring-opening reaction from N-Methylboldinium halide (4) to form N-Methylsecoboldine (5) 19 Scheme 7. Synthesis of N-Dimethylsecoboldinium chloride (7) 20 Scheme 8. Mechanism of the acetylation from N-Methylsecoboldine (5) to N-Methyldiacetylsecoboldine (6) 21 Scheme 9. Mechanism of N-methylation, then hydrolysis from N-Methyldiacetylsecoboldine (6) to N-Dimethylsecoboldinium chloride (7) 21 Scheme 10. Synthesis of Secopredicentrine (8) and 2a-Methyl-7-O-methyllitebamine (9) 22 Scheme 11. Mechanism of the ring-opening reaction and methylation from Predicentrine (B) to Secopredicentrine (8) 23 Scheme 12. Mechanism of the cyclization from Secopredicentrine (8) to 2a-Methyl-7-O-methyllitebamine (9) 23 Scheme 13. Mechanism of N-acetylation of crude Laurolitsine to form N-Acetyllaurolitsine (10) 24 Scheme 14. Mechanism of ring-opening reaction of N-Acetyllaurolitsine (10) and hydrolysis of N-Acetylsecolaurolitsine (11) to form Secolaurolitsine (12) 25 Scheme 15. Preparation of pure Laurolitsine via chemical methods 26 Scheme 16. Model Study之實驗設計 26 Scheme 17. Reaction from reference 19 27 Scheme 18. Mechanism of Mannich reaction on Secolaurolitsine (12) to form Norlitebamine (13) 29 Scheme 19. Reaction of Series-1 derivatives 30 Scheme 20. Mechanism of the Solvolysis reaction from Boldine (1) to Secoboldine (14) 32 Scheme 21. Mannich reaction of Secoboldine (14) to form 2a-Methyllitebamine (15) and 2a-Ethyllitebamine (16) 34 圖目錄(List of Figures) Figure 1.痛風之全球性盛行率 1 Figure 2. Hypoxanthine and xanthine are oxidized by xanthine oxidase to form uric acid which might cause hyperuricemia and/or gout. 2 Figure 3. Allopurinol與Febuxostat皆屬於黃嘌呤氧化酶抑制劑，為痛風之第一線治療藥物 3 Figure 4.黃嘌呤氧化酶之單體結構 4 Figure 5. Allopurinol與黃嘌呤氧化酶之細部交互作用 5 Figure 6. 頭花香苦草(Hyptis rhomboides)標本(國立台灣大學植物標本館) 5 Figure 7. 化合物Ⅰ–ⅩⅢ之結構 6 Figure 8. Aporphine衍生物之結構 9 Figure 9. Aporphine與Secoaporphine之結構 11 Figure 10. N-Methyllauroletenine (A)與Predicentrine (B)之結構 11 Figure 11. 所設計之系列一與二之化合物結構 12 Figure 12. 波多樹與台灣雅楠 14 Figure 13. Inhibition (%) of xanthine oxidase by compounds 5, 7, 8, 9, 13, 15, and 16 36 Figure 14. IR spectrum of Diacetylboldine (2) 41 Figure 15. UV spectrum of Diacetylboldine (2) 41 Figure 16. ESI-MS spectrum of Diacetylboldine (2) 41 Figure 17. IR spectrum of N-Methyldiacetylboldinium iodide (3) 43 Figure 18. UV spectrum of N-Methyldiacetylboldinium iodide (3) 43 Figure 19. ESI-MS spectrum of N-Methyldiacetylboldinium iodide (3) 43 Figure 20. IR spectrum of N-Methylboldinium halide (4) 45 Figure 21. UV spectrum of N-Methylboldinium halide (4) 45 Figure 22. ESI-MS spectrum of N-Methylboldinium halide (4) 45 Figure 23. IR spectrum of N-Methylsecoboldine (5) 47 Figure 24. UV spectrum of N-Methylsecoboldine (5) 47 Figure 25. ESI-MS spectrum of N-Methylsecoboldine (5) 47 Figure 26. IR spectrum of N-Dimethylsecoboldinium chloride (7) 50 Figure 27. UV spectrum of N-Dimethylsecoboldinium chloride (7) 50 Figure 28. ESI-MS spectrum of N-Dimethylsecoboldinium chloride (7) 50 Figure 29. IR spectrum of Secopredicentrine (8) 52 Figure 30. UV spectrum of Secopredicentrine (8) 52 Figure 31. ESI-MS spectrum of Secopredicentrine (8) 52 Figure 32. IR spectrum of 2a-Methyl-7-O-methyllitebamine (9) 54 Figure 33. UV spectrum of 2a-Methyl-7-O-methyllitebamine (9) 54 Figure 34. ESI-MS spectrum of 2a-Methyl-7-O-methyllitebamine (9) 54 Figure 35. IR spectrum of N-Acetyllaurolitsine (10) 56 Figure 36. UV spectrum of N-Acetyllaurolitsine (10) 56 Figure 37. ESI-MS spectrum of N-Acetyllaurolitsine (10) 56 Figure 38. IR spectrum of N-Acetylsecolaurolitsine (11) 58 Figure 39. UV spectrum of N-Acetylsecolaurolitsine (11) 58 Figure 40. ESI-MS spectrum of N-Acetylsecolaurolitsine (11) 58 Figure 41. IR spectrum of Secolaurolitsine (12) 60 Figure 42. UV spectrum of Secolaurolitsine (12) 60 Figure 43. ESI-MS spectrum of Secolaurolitsine (12) 60 Figure 44. IR spectrum of Norlitebamine (13) 62 Figure 45. UV spectrum of Norlitebamine (13) 62 Figure 46. ESI-MS spectrum of Norlitebamine (13) 62 Figure 47. IR spectrum of Secoboldine (14) 64 Figure 48. UV spectrum of Secoboldine (14) 64 Figure 49. ESI-MS spectrum of Secoboldine (14) 64 Figure 50. IR spectrum of 2a-Methyllitebamine (15) 66 Figure 51. UV spectrum of 2a-Methyllitebamine (15) 66 Figure 52. ESI-MS spectrum of 2a-Methyllitebamine (15) 66 Figure 53. IR spectrum of 2a-Ethyllitebamine (16) 68 Figure 54. UV spectrum of 2a-Ethyllitebamine (16) 68 Figure 55. ESI-MS spectrum of 2a-Ethyllitebamine (16) 68 Figure 56. 96-well plate sample arrangement (n = 3) 70 Figure 57. 1H NMR spectrum of Diacetylboldine (2) (CD3OD, 200 MHz) 75 Figure 58. 1H NMR spectrum of N-Methyldiacetylboldinium iodide (3) (CD3OD, 200 MHz) 76 Figure 59. 1H NMR spectrum of N-Methylboldinium halide (4) (CD3OD, 200 MHz) 77 Figure 60. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of N-Methylboldinium halide (4) (CD3OD, 50 MHz) 78 Figure 61. 1H NMR spectrum of N-Methylsecoboldine (5) (CD3OD, 200 MHz) 79 Figure 62. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of N-Methylsecoboldine (5) (CD3OD, 50 MHz) 80 Figure 63. 1H NMR spectrum of N-Methyldiacetylsecoboldine (6) (CDCl3, 200 MHz) 81 Figure 64. 1H NMR spectrum of N-Dimethylsecoboldinium chloride (7) (CD3OD, 400 MHz) 82 Figure 65. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of N-Dimethylsecoboldinium chloride (7) (CD3OD, 50 MHz) 83 Figure 66. 1H NMR spectrum of Secopredicentrine (8) (CDCl3, 200 MHz) 84 Figure 67. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of Secopredicentrine (8) (CD3OD, 50 MHz) 85 Figure 68. 1H NMR spectrum of 2a-Methyl-7-O-methyllitebamine (9) (CDCl3, 200 MHz) 86 Figure 69. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of 2a-Methyl-7-O-methyllitebamine (9) (CDCl3, 50 MHz) 87 Figure 70. 1H NMR spectrum of N-Acetyllaurolitsine (10) (CD3OD, 200 MHz) 88 Figure 71. 1H NMR spectrum of N-Acetylsecolaurolitsine (11) (CD3OD, 200 MHz) 89 Figure 72. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of N-Acetylsecolaurolitsine (11) (CD3OD, 50 MHz) 90 Figure 73. 1H NMR spectrum of Secolaurolitsine (12) (CD3OD, 200 MHz) 91 Figure 74. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of Secolaurolitsine (12) (CD3OD, 50 MHz) 92 Figure 75. 1H NMR spectrum of Norlitebamine (13) (CD3OD, 200 MHz) 93 Figure 76. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of Norlitebamine (13) (CD3OD, 50 MHz) 94 Figure 77. 1H NMR spectrum of Secoboldine (14) (CD3OD, 200 MHz) 95 Figure 78. 1H NMR spectrum of 2a-Methyllitebamine (15) (CD3OD, 200 MHz) 96 Figure 79. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of 2a-Methyllitebamine (15) (CD3OD, 50 MHz) 97 Figure 80. 1H NMR spectrum of 2a-Ethyllitebamine (16) (CD3OD, 600 MHz) 98 Figure 81. 13C NMR spectrum (BBD, button; DEPT-135, middle; DEPT-90, top) of 2a-Ethyllitebamine (16) (CD3OD, 150 MHz) 99 | |
| dc.language.iso | zh-TW | |
| dc.subject | 環化 | zh_TW |
| dc.subject | 黃嘌呤氧化? | zh_TW |
| dc.subject | 黃嘌呤氧化?抑制活性 | zh_TW |
| dc.subject | 高尿酸血症 | zh_TW |
| dc.subject | 痛風 | zh_TW |
| dc.subject | 氮原子自動質子化 | zh_TW |
| dc.subject | Hyperuricemia | en |
| dc.subject | Xanthine oxidase | en |
| dc.subject | Inhibition of xanthine oxidase | en |
| dc.subject | Cyclization | en |
| dc.subject | Auto-protonation of N-containing Aporphine | en |
| dc.subject | Gout | en |
| dc.title | Boldine與Laurolitsine衍生物之製備與抑制黃嘌呤氧化酶活性之研究 | zh_TW |
| dc.title | Preparation and Anti-Xanthine Oxidase Activity of Derivatives of Boldine and Laurolitsine | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李安榮(An-Rong Lee),張溫良(Wen-Liang Chang) | |
| dc.subject.keyword | 黃嘌呤氧化?,高尿酸血症,痛風,氮原子自動質子化,環化,黃嘌呤氧化?抑制活性, | zh_TW |
| dc.subject.keyword | Xanthine oxidase,Hyperuricemia,Gout,Auto-protonation of N-containing Aporphine,Cyclization,Inhibition of xanthine oxidase, | en |
| dc.relation.page | 99 | |
| dc.identifier.doi | 10.6342/NTU201902472 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-05 | |
| 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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