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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李水盛 | |
dc.contributor.author | Yi-Pin Lu | en |
dc.contributor.author | 盧怡頻 | zh_TW |
dc.date.accessioned | 2021-06-16T02:39:04Z | - |
dc.date.available | 2020-07-01 | |
dc.date.copyright | 2015-09-24 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-23 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54077 | - |
dc.description.abstract | 本論文包括二個部分: 第一部分 頭花香苦草葉部成分之研究 唇形科(Labiatae)香苦草屬(Hyptis)的植物主要分布在全球熱帶以及亞熱帶地區。本研究以Hyptis rhomboids Mart. Gal.(頭花香苦草)葉部乙醇萃取成分是否具有抑制黃嘌呤氧化酵素的活性為研究方向,利用Sephadex LH-20管柱、矽膠管柱、低壓逆相層析管柱以及半製備高壓液相層析管柱進行分離。自乙醇萃取物中分離並鑑定出十一個化合物,其中包括caffeic acid、kaempferol 3-O-glucoside、rosmarinic acid、rosmarinic acid methyl ester、7-hydroxy-5,8,4'-trimethoxyflavone、genkwanin、nicotiflorin、ethyl caffeoate、nepetoidin A、nepetoidin B、 kaempferol 。活性結果顯示十一個化合物具有微弱的抑制效果,其中具有中等抑制活性的為caffeic acid (IC50 77.0 uM),nepetoidin B (IC50 14.1 uM)及kampferol (IC50 7.1 uM)則有較佳抑制活性。 第二部分 色原酮衍生物之製備 黃酮類化合物根據文獻以及第一部分的研究結果顯示此類化合物的架構對黃嘌呤氧化酵素有弱抑制活性,接著以電腦分子模擬方式預測色原酮衍生物對於黃嘌呤氧化酵素有結合能力,因此以此系列化合物為合成目標,進行其結構與抑制黃嘌呤氧化酵素活性之探討。此系列化合物先以phloroglucinol為起始物,和丙醯氯在強路易士酸中進行Friedel-Craft反應,接著以不同碳數之酸酐進行酯化反應,再進行醇醛縮合及脫水而得在2號位置上具甲基-戊基取代的15a-e終產物。藥物活性測試結果顯示產物15a-e對於黃嘌呤氧化酵素有微弱的抑制效果。本部分研究結果中,色原酮在2號位置上接有5碳結構具有最好的抑制活性。 關鍵詞: 頭花香苦草、黃嘌呤氧化酵素、色原酮衍生物、Friedel-Craft反應 | zh_TW |
dc.description.abstract | This dissertation includes two parts:
Part 1. Chemical investigation of the leaves of Hyptis rhomboids Mart. Gal. The Hyptis(Labiatae)plants are mainly distributed in the tropical and subtropical regions. This research was aimed to discover the ingredients of the EtOH extract of Hyptis rhomboids (leaves) with the inhibitory activity against xanthine oxidase by chromatographic methods (Sephadex LH-20, silica gel, Lobar RP-18, semipreparative HPLC). Eleven compounds in total were isolated including caffeic acid, kaempferol 3-O-glucoside, rosmarinic acid, rosmarinic acid methyl ester, 7-hydroxy-5,8,4'-trimethoxyflavone, genkwanin, nicotiflorin, ethyl caffeoate, nepetoidin A, nepetoidin B and kaempferol. Bioassay of these isolates against xanthine oxidase revealed that only caffeic acid (IC50 77.0 uM), nepetoidin B (IC50 14.1 uM) and kaempferol (IC50 7.1 uM) possess moderate inhibitory activity. Part 2. Preparation of chromone derivatives According to reference and the results of part 1 study, flavonoids appears to reveal the inhibitory activity against xanthine oxidase. Since the chromone derivatives were predicted to have moderate inhibitory activity against this enzyme by computer assisted docking study, this second part study was aimed to prepare such compounds and verify whether their activity is correlated well with that predicted. The Friedel-Craft acylation of phloroglucinol with propionyl chloride yielded the key intermediate, flopropione. Esterification of flopropione with various acid anhydride, followed by aldol condensation and dehydration, gave the final products 15a-e with different carbon number on C2 position. The results of the inhibitory activity of 15a-e against xanthine oxidase reveal weak activity. Of them, 15e with a pentyl substitution at the C-2 position shows the best inhibitory activity. Key words:Hyptis rhomboids Mart. Gal., xanthine oxidase, chromone derivatives, Friedel-Craft acylation | en |
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dc.description.tableofcontents | 總目錄 中文摘要…………………………………………………………………………....…I 英文摘要………………………………………………………………...…...........….II 目錄………..............................................................................................................…Ⅳ 流程圖目錄 (List of Schemes)…...............................................................................Ⅷ 表目錄 (List of Tables)……...………........................................................……...….Ⅷ 圖目錄 (List of Figures)……..................................................................................…Ⅸ 辭彙 (Glossary)………………………………………………………..…………….XI 目錄 第一章 頭花香苦草葉部成分之研究 1 1. 緒論及研究目的 1 1.1 研究目的 1 1.2 頭花香苦草之簡介 2 1.3 香苦草屬(Hyptis)植物成分之文獻回顧 3 1.4 痛風與臨床治療藥物 18 1.4.1 痛風之簡介 18 1.4.2 痛風治療藥物 19 1.4.3 黃嘌呤氧化酵素抑制劑(xanthine oxidase inhibitor) 20 1.4.3.1 Allopurinol 21 1.4.3.2 Febuxostat 21 1.4.3.3 黃酮類(Flavonoids) 22 2. 實驗結果與討論 23 2.1 苯丙烷(Phenylpropanoid)成分1, 3-4, 8-10之結構解析 25 2.1.1 Caffeic acid (1)之結構解析 25 2.1.2 Ethyl caffeoate (8)之結構解析 25 2.1.3 Rosmarinic acid (3)之結構解析 27 2.1.4 Rosmarinic acid methyl ester (4)之結構解析 27 2.1.5 Nepetoidin A (9)之結構解析 29 2.1.6 Nepetoidin B (10)之結構解析 29 2.2 黃酮類(Flavonoid)成分2, 5-7, 11之結構解析 31 2.2.1 Kaempferol 3-O-b-glucoside (2)之結構解析 31 2.2.2 Nicotiflorin (7)之結構解析 33 2.2.3 7-Hydroxy-5,8,4′-trimethoxyflavone (5)之結構解析 35 2.2.4 Genkwanin (6)之結構解析 37 2.2.5 Kaempferol (11)之結構解析 37 2.3 黃嘌呤氧化酵素抑制活性測試結果 39 2.4 結論 40 3. 實驗部分 41 3.1 儀器與材料 41 3.1.1 理化性質測定儀器 41 3.1.2 成分分離之儀器與材料 41 3.1.3 試劑與溶媒 42 3.1.4 Xanthine oxidase assay之試劑與儀器 42 3.2 植物來源 43 3.3 頭花香苦草葉部成分萃取與純化 43 3.3.1 乙酸乙酯可溶部分之分離 44 3.3.1.1 化合物1之純化 44 3.3.1.2 化合物2之純化 44 3.3.1.3 化合物3和4之純化 44 3.3.2 乙腈可溶部分之分離 46 3.3.2.1 化合物5之純化 46 3.3.2.2 化合物6-8之純化 46 3.3.2.3 化合物9-11之純化 46 3.4 化合物之物理數據 48 3.5 黃嘌呤氧化酵素抑制活性測試 50 3.5.1 原理 50 3.5.2 實驗方法 50 3.5.2.1 試劑配置 50 3.5.2.2 實驗步驟 51 3.5.2.3 IC50之計算 52 第二章 :色原酮衍生物之製備 53 1. 緒論及研究目的 53 1.1 研究目的 53 1.2 黃酮類成分之抑制黃嘌呤氧化酵素活性文獻回顧 54 2. 實驗結果與討論 66 2.1 實驗設計 66 2.2 化合物的合成 67 2.2.1 Flopropione (13-1) 之製備與研究 (Scheme 7) 67 2.2.2 化合物 14a-e之製備 (Scheme 8) 69 2.2.3 化合物 15a-e之製備 (Scheme 9) 70 2.3 結論 72 3. 實驗部分 73 3.1 儀器與材料 73 3.1.1 理化性質測定儀器 73 3.1.2 成分分離之儀器與材料 73 3.1.3 試劑與溶媒 74 3.2 色原酮衍生物之製備與物理數據 75 3.2.1 Flopropione (13-1)之製備 75 3.2.2 Compounds 14a-e之製備 77 3.2.3 Compounds 15a-c之製備 79 3.2.4 Compounds 15d-e之製備 81 3.3 黃嘌呤氧化酵素抑制活性測試 83 3.3.1 原理 83 3.3.2 實驗方法 83 3.3.2.1 試劑配置 83 3.3.2.2 實驗步驟 84 3.3.2.3 IC50之計算 85 參考資料 86 附圖 91 流程圖目錄 Scheme 1. Fractionation of the EtOH extract of Hyptis rhomboides Mart. Gal. 43 Scheme 2. Separation scheme of EtOAc-soluble part of the EtOH extract of Hyptis rhomboides Mart. Gal. leaves 45 Scheme 3. Separation scheme of ACN-soluble part of the EtOH extract of Hyptis rhomboides Mart. Gal. leaves 47 Scheme 4. Reaction catalyzed by xanthine oxidase 50 Scheme 5. Structure of compounds for computer assisted molecular docking 53 Scheme 6. Preparation plane of 15 series 66 Scheme 7. Preparation of compound 13-1 67 Scheme 8. Preparation of compounds 14a-e 69 Scheme 9. Preparation of compounds 15a-e 70 Scheme 10. Reaction catalyzed by xanthine oxidase 83 表目錄 Table 1. Compounds isolated from Hyptis plants 3 Table 2. 一般典型的痛風病人在臨床上的發展 18 Table 3. 治療痛風藥物種類作用機轉、副作用、劑量 19 Table 4. Caculated total amount of compounds 1-11 23 Table 5. 1H and 13C NMR data of compound 1 (CD3OD)、compound 8 (1H NMR CD3OD, 13C NMR acetone-d6) 26 Table 6. 1H and 13C NMR data of compounds 3 and 4 (CD3OD) 28 Table 7. 1H and 13C NMR data of compounds 9 and 10 (CD3OD) 30 Table 8. 1H and 13C NMR data of compound 2 (CD3OD) 32 Table 9. 1H and 13C NMR data of compound 7 (CD3OD) 34 Table 10. 1H and 13C NMR data of compound 5 (CDCl3) 36 Table 11. 1H and 13C NMR data of compound 6 (DMSO-d6) and 11 (CD3OD) 38 Table 12. Compounds inhibitory activity against xanthine oxidase 54 Table 13. 1H and 13C NMR data of compound 13-1 (CD3OD) 68 Table 14. 1H and 13C NMR data of compounds 15a-e (CD3OD) 71 Table 15. Yield of compounds 14a-14e 77 圖目錄 Figure 1. 頭花香苦草植株(a)莖葉部分、(b)莖切部、(c)葉部、(d)花、(e)果實 2 Figure 2. Lactones, pyrones, brevipolides isolated from Hyptis plants 9 Figure 3. Phenylpropanoids isolated from Hyptis plants 10 Figure 4. Terpenoids isolated from Hyptis plants (A) 11 Figure 5. Terpenoids isolated from Hyptis plants (B) 12 Figure 6. Terpenoids isolated from Hyptis plants (C) 13 Figure 7. Terpenoids isolated from Hyptis plants (D) 14 Figure 8. Terpenoids isolated from Hyptis plants (E) 15 Figure 9. Terpenoids isolated from Hyptis plants (F) 16 Figure 10. Flavonoids and other compounds isolated from Hyptis plants 17 Figure 11. Mechanism of action of xanthine oxidase 20 Figure 12. (a) The structure of allopurinol; (b) The interaction between allopurinol and xanthine oxidase 21 Figure 13. (a) The structure of febuxostat; (b) The interaction between febuxostat and xanthine oxidase 22 Figure 14. (a) Essential structure of flavonoids; (b) The interaction between quercetin and xanthine oxidase 22 Figure 15. Structures of compounds 1-11 from the leaves of Hyptis rhomboids Mart. Gal. 24 Figure 16. Xanthine oxidase inhibition assay of compounds 1-11 39 Figure 17. 孔微量測試盤上各組測試樣品的排列情形(n=3) 52 Figure 18. Inhibitory activity of flavones against xanthine oxidase 59 Figure 19. Inhibitory activity of flavonols, isoflavones, flavanonols and flavanones against xanthine oxidase 60 Figure 20. Inhibitory activity of flavanols and apigenin derivatives against xanthine oxidase 61 Figure 21. Inhibitory activity of gallic acid derivatives and naphthoflavones against xanthine oxidase 62 Figure 22. Inhibitory activity of aza-flavones against xanthine oxidase 63 Figure 23. Inhibitory activity of phenylpropanoids against xanthine oxidase 64 Figure 24. Inhibitory activity of others against xanthine oxidase 65 Figure 25. Structure of compounds 15a-e 70 Figure 26. Xanthine oxidase inhibition of compounds 15a-e 72 Figure 27. Structure of compounds 13-1-13-3 75 Figure 28. 孔微量測試盤上各組測試樣品的排列情形(n=3) 85 附圖目錄 (List of supporting figures) Figure S 1. 1H-NMR spectrum of compound 1 (CD3OD, 200 MHz) 95 Figure S 2. 13C-NMR spectra of compound 1 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 96 Figure S 3. 1H-NMR spectrum of compound 2 (CD3OD, 200 MHz) 97 Figure S 4. 13C-NMR spectra of compound 2 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 100 MHz) 98 Figure S 5. 1H-NMR spectrum of compound 3 (CD3OD, 200 MHz) 99 Figure S 6. 13C-NMR spectra of compound 3 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 100 Figure S 7. 1H-NMR spectrum of compound 4 (CD3OD, 200 MHz) 101 Figure S 8. 13C-NMR spectra of compound 4 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 102 Figure S 9. 1H-NMR spectrum of compound 5 (CDCl3, 200 MHz) 103 Figure S 10. 13C-NMR spectra of compound 5 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CDCl3, 100 MHz) 104 Figure S 11. HMBC spectrum of compound 5 (CDCl3, 600 MHz) 105 Figure S 12. 1H-NMR spectrum of compound 6 (DMSO-d6, 200 MHz) 106 Figure S 13. 13C-NMR spectra of compound 6 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (DMSO-d6, 50 MHz) 107 Figure S 14. 1H-NMR spectrum of compound 7 (CD3OD, 400 MHz) 108 Figure S 15. 13C-NMR spectra of compound 7 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 100 MHz) 109 Figure S 16. 1H-NMR spectrum of compound 8 (CD3OD, 200 MHz) 110 Figure S 17. 13C-NMR spectra of compound 8 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (acetone-d6, 50 MHz) 111 Figure S 18. 1H-NMR spectrum of compound 9 (CD3OD, 200 MHz) 112 Figure S 19. 13C-NMR spectra of compound 9 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 100 MHz) 113 Figure S 20. 1H-NMR spectrum of compound 10 (CD3OD, 200 MHz) 114 Figure S 21. 13C-NMR spectra of compound 10 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 115 Figure S 22. 1H-NMR spectrum of compound 11 (CD3OD, 200 MHz) 116 Figure S 23. 13C-NMR spectra of compound 11 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 100 MHz) 117 Figure S 24. 1H-NMR spectrum of compound 13-1 (CD3OD, 200 MHz) 118 Figure S 25. 13C-NMR spectra of compound 13-1 (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 119 Figure S 26. 1H-NMR spectrum of compound 13-2 (CD3OD, 200 MHz) 120 Figure S 27. 1H-NMR spectrum of compound 13-2 (CD3OD, 200 MHz) 121 Figure S 28. 1H-NMR spectrum of compound 14a (CDCl3, 200 MHz) 122 Figure S 29. 1H-NMR spectrum of compound 14b (CDCl3, 200 MHz) 123 Figure S 30. 1H-NMR spectrum of compound 14c (CDCl3, 200 MHz) 124 Figure S 31. 1H-NMR spectrum of compound 14d-A (CD3OD, 200 MHz) 125 Figure S 32. 1H-NMR spectrum of compound 14e-A (CD3OD, 200 MHz) 126 Figure S 33. 1H-NMR spectrum of compound 15a (CD3OD, 200 MHz) 127 Figure S 34. 13C-NMR spectra of compound 15a (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 128 Figure S 35. 1H-NMR spectrum of compound 15a (CDCl3, 200 MHz) 129 Figure S 36. 13C-NMR spectra of compound 15a (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CDCl3, 100 MHz) 130 Figure S 37. IR spectrum of compound 15a 131 Figure S 38. 1H-NMR spectrum of compound 15b (CD3OD, 200 MHz) 132 Figure S 39. 13C-NMR spectra of compound 15b (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 133 Figure S 40. IR spectrum of compound 15b 134 Figure S 41. 1H-NMR spectrum of compound 15c (CD3OD, 200 MHz) 135 Figure S 42. 13C-NMR spectra of compound 15c (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 136 Figure S 43. IR spectrum of compound 15c 137 Figure S 44. 1H-NMR spectrum of compound 15d (CD3OD, 200 MHz) 138 Figure S 45. 13C-NMR spectra of compound 15d (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 139 Figure S 46. IR spectrum of compound 15d 140 Figure S 47. 1H-NMR spectrum of compound 15e (CD3OD, 200 MHz) 141 Figure S 48. 13C-NMR spectra of compound 15e (BBD: bot.; DEPT-90: top; DEPT-135: mid.) (CD3OD, 50 MHz) 142 Figure S 49. IR spectrum of compound 15e 143 | |
dc.language.iso | zh-TW | |
dc.title | 頭花香苦草葉部成分之研究及色原酮衍生物之製備 | zh_TW |
dc.title | Chemical investigation of Hyptis rhomboids leaves and preparation of chromone derivatives | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳繼明,張嘉銓 | |
dc.subject.keyword | 頭花香苦草,黃嘌呤氧化酵素,色原酮衍生物,Friedel-Craft反應, | zh_TW |
dc.subject.keyword | hyptis rhomboids Mart. Gal.,xanthine oxidase,chromone derivatives,Friedel-Craft acylation, | en |
dc.relation.page | 143 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-07-23 | |
dc.contributor.author-college | 藥學專業學院 | 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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