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研究生:陳拯裕
研究生(外文):Cheng-Yu Chen
論文名稱:大葉骨碎補與姬蕨化學成分及活性評估之探討
論文名稱(外文):Chemical Investigation and Bioactivity of Davallia formosana Hayata and Hypolepis punctate (Thunb.) Mett
指導教授:黃偉展黃偉展引用關係
口試委員:李水盛謝博軒李美賢
口試日期:2015-07-14
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:藥學系(碩博士班)
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:137
中文關鍵詞:大葉骨碎補姬蕨高尿酸血症蝕骨細胞葡萄糖攝入
外文關鍵詞:Davallia formosana (Davalliaceae)Hypolepis punctata (Dennstaediaaceae)HypouricemicOsteoclastogenesisGlucose uptake
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大葉骨碎補 (Davallia formosana Hayata)為骨碎補科 (Davalliaceae) 骨碎補屬 (Davallia),為民間常用治療骨科藥材之一。本研究探討大葉骨碎補之根部成分對高尿酸血症及抑制蝕骨細胞形成,從大葉骨碎補之根部分離出 20個化合物,包含2個新化合物: epiphyllocoumarin-3-O-β-D-allopyranoside (4)與8-(2-pyrro-lidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5),及18個已知化合物。其中,化合5,7-dihydroxy-6-C-glucosy-chromone (1)、eriodictyol-6-C-β-D-glucopyranoside (2)、naringenin-6-C-β-D-glucopyranoside (3)、eriodicytyol-8-
C-β-D-glucopyranoside (10)、davallioside A (11)davallioside B (12)、caffeic acid-4-O-β-D-glucopyranoside (13)、p-coumaric acid-4-O-β-D-glucopyranoside (14)、protocatechuic acid (15)、4-hydroxy-3,5-dimethylbenzoic acid (16)、vanillic acid (17)及4-hydroxy-3-aminobenzoic acid (18)為從大葉骨碎補之根部首次所分離出之化合物。從體外活性評估實驗結果顯示,naringenin-6-C-
β-D-glucopyranoside (3) (IC50 57.4 M)與 epiphyllocoumarin-3-O-β-D-allopyranoside (4) (IC50 124 M)可抑制XOD之活性,並分別在小鼠動物模式中亦可降低血清尿酸濃度41.7 -46.0 %。另外,caffeic acid-4-O-β-D-glucopyranoside (13)、protocatehuic acid (15) 與 epicatechin (6)於10 μg/ml濃度下可抑制由RAKNL所誘導的蝕骨細胞形成。
姬蕨 (Hypolepis punctata (Thunb.) Mett.)屬於多年原生草本蕨類植物,為碗蕨科 (Dennstaediaaceae),姬蕨屬(Hyplepis)。從台灣產蕨類植物降血糖活性之篩選當中,姬蕨甲醇萃取物具有降血糖活性。經由姬蕨全草甲醇萃取物中,分離出23個化合物,包含3個新化合物: (+)-3-O-caffeoyl-L-glyceric acid (22)、(+)-3-O-p-coumaroyl-L-glyceric acid (23) 及quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D-glucopyranoside (38),及20個已知化合物,其中化合物(-)-4-O-caffeoyl-threonic acid (24)、chlorogenic acid (25)、6-O-p-coumaroyl-β-D-glucopyranoside (26)、coniferin (27)、lanicepside B (28)、lanicepside A (29)、quercetin (34)、quercetin-3-O-β-D-glucopyranoside (35)、kaempherol-3-O-β-D-glucopyranoside (36)與rutin (37),為姬蕨植物首次分離出之化合物。利用2-NBDG評估化合物是否對L6骨骼肌細胞有促進葡萄糖攝取效果,實驗結果顯示,化合物 lanicepside A (29)、 (-)-(7S,8R)-dihydro dehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside (31)、(-)-isolariciresinol-4-O-β-D-glucopyranoside (32)、quercetin (34)與kaempherol-3-O-β-D-glucopyranoside (36)在濃度1 M劑量下,有促進L6細胞攝取葡萄糖。
本實驗從大葉骨碎補及姬蕨共分離出43個化合物,其中化合物4、5、22、23與38為新化合物。化合物(-)-epicatechin-3-O-β-D-allopyranoside (9)為大葉骨碎補主要成分,而pterosin A (39)為姬蕨主要成分。在高尿酸血症評估中,epiphyllocoumarin-3-O-β-D-allopyranoside (4)可能是透過抑制XOD,達到降低血清尿酸濃度。除此之外,在抑制蝕骨細胞形成之活性探討,以caffeic acid-4-O-β-D-glucopyranoside (13)效果最佳 (26.8%)。同時,在促進L6骨骼肌攝入葡萄糖初步篩選,以lanicepside A (29) (157%)及quercetin (34) (153%)效果相較其它化合物較佳,其中化合物29則為首次發現具有glucose uptake的促進效果。
Davallia formosana Hayata (Davalliaceae) is a popular herbal medicine used to treat osteoporosis. The aim of this study was to investigate the anti-hyperuricemic and anti-
osteoclastogenic actions of D. formosana. The twenty isolated photochemical, including two novel compounds, epiphyllocoumarin-3-O-β-D-allopyranoside (4) and 8-(2-pyrro-lidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5), and eighteen known compounds were examined on the ability to inhibit xanthine oxidase (XOD) activity. Furthermore, compounds 1-3 and 10-18 were reported from D. formosana for the first time. The results indicated that compounds 3 (IC50 57.4 M) and 4 (IC50 124 M) significantly inhibited XOD activity in vitro, and reduced 41.7 - 46.0 % serum uric acid levels in vivo , respectively. On the other hand, caffeic acid-4-O-β-D-glucopyranoside (13), protocatehuic acid (15) and epicatechin (6) were able to inhibit RANKL-induced osteoclastogenesis.
The MeOH extract of Hypolepis punctata (Dennstaediaaceae) were found to anti-hyperglycemic during preliminary screening. Twenty-three phytochemicals., including the three newly discovered compounds, (+)-3-O-caffeoyl-L-glyceric acid (22), (+)-3-O-p-coumaroyl-L-glyceric acid (23) and quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6)) -β-D-glucopyranoside (38), and twenty known compounds were isolated from H. punctata. In addition, compounds 24 -29 and 34-37 were identified in H. punctata for the first time.The compounds 21-43 were evaluated on the ability to stimulate glucose uptake activity in L6 myotube cells. The results showed that lanicepside A (29), (-)-(7S,8R)-dihydro-dehydrodiconiferyl alcohol 4-O-β-D-glucopyranoside (31), (-)-isolariciresinol-4-O-β-D-glucopyranoside (32), quercetin (34) and kaempherol-3-O-β-D-glucopyranoside (36) significantly increased glucose uptake.
The studies were forty-three photochemical isolated from D. formosana.and H. punctata., including five novel compounds, piphyllocoumarin-3-O-β-D-allopyranoside (4) and 8-(2-pyrro-lidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5), (+)-3-O-caffeoyl-L-glyceric acid (22), (+)-3-O-
p-coumaroyl-L-glyceric acid (23) and quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6)) -β-D-glucopyranoside (38). The (-)-epicatechin-3-O-β-D-allopyranoside (9) and pterosin A (39) were major composition from D. formosana.and H. punctata., respectively. The results indicated that epiphyllocoumarin-3-O-β-D-allopyranoside (4) significantly inhibited XOD activity in vitro, and reduced serum uric acid levels in vivo. On the other hand, caffeic acid-4-O-β-D- glucopyranoside (13) was able to inhibit RANKL-induced osteoclastogenesis. Among the compounds isolated from H. Punctata, lanicepside A (29) and quercetin (34) were demonstrated to enhance glucose uptake to 157 % and 153%, respectively.
中文摘要 I
英文摘要 III
圖目錄 VIII
表目錄 XII
名詞縮寫 XIII

第一章、緒論 1
第一節、研究背景 1
1-1.1尿酸及高尿酸血症 1
1-1.2骨質疏鬆症的簡介 3
1-1.3糖尿病簡介 6
1-1-3.1 糖尿病分類 6
1-1-3.2 葡萄糖攝入路徑 7
第二節、標的植物研究之回顧 9
1-2.1大葉骨碎補成分之化學結構與藥理活性文獻回顧 9
1-2-1.1 大葉骨碎補之植物簡介 9
1-2-1.2、大葉骨碎補化學成分及藥理研究文獻之概要 11
1-2.2姬蕨成分之化學結構與藥理活性文獻回顧 17
1-2-2.1姬蕨之植物簡介 17
1-2-2.2姬蕨化學成分及藥理研究文獻之概要 29
第三節、研究動機及目的 22
第二章、研究結果 23
第一節、植物抽取與化學成分之分離 23
2-1.1大葉骨碎補成分之分離 23
2-1.2姬蕨成分之分離 24
第二節、化學結構鑑定 25
2-2.1已知化合物之鑑定 25
2-2.2.新化合物之構造解析 30
2-2-2.1Epiphyllocoumarin-3-O-β-D-allopyranoside (4)之結構解析
30
2-2-2.2 8-(2-Pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5)之結構解析 40
2-2-2.3 (+)-3-O-Caffeoyl-L-glyceric acid (22)之結構解析 50
2-2-2.4 (+)-3-O-p-Coumaroyl-L-glyceric acid (23)之結構解析
58
2-2-2.5 Quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D- glucopyranoside (38)之結構解析 65
第三節、生物活性評估 73
2-3.1大葉骨碎補之活性 73
2-3-1.1抑制黃嘌呤氧化酶活性之評估 73
2-3-1.2急性高尿酸血症小鼠模型 73
2-3-1.2分子嵌合( Molecular docking ) 76
2-3-1.3 抑制蝕骨細胞形成 78
2-3.2姬蕨之活性 80
2-3-2.1 促進L6肌肉細胞葡萄糖攝入 (glucose uptake) 之評估 80
第三章、討論 83
第一節、大葉骨碎補成分與活性 83
3-1.1大葉骨碎補根部成分之特徵 83
3-1.2 Epiphyllocoumarin-3-O-β-D-allopyranoside (5)降低血清尿酸
89
3-1.3 Caffeic acid-4-O-β-D-glucopyranoside抑制蝕骨細胞形成 90
第二節、姬蕨成分與活性 92
3-2.1姬蕨成分之特徵 92
3-2.2 Lanicepside A促進L6細胞葡萄糖攝入 98
第四章、實驗材料與方法 100
4-1.儀器 100
4-2.層析法 100
4-3.一般化學溶媒及試藥 101
4-4.大葉骨碎補成分之分離流程 101
4-5.姬蕨成分之分離流程 104
4-6.活性評估試驗 106
4-6.1 XOD活性測試 106
4-6.2降尿酸動物實驗 106
4-6.3黃嘌呤氧化酶的分子對接 107
4-6.4蝕骨細胞(osteoclast)的分化 107
4-6.5 L6肌細胞對葡萄糖攝入作用 107
4-7. 各化合物之物理數據 108
參考文獻 126
論文發表 137
圖目錄
Figure 1. The regulation of glucose transporter by insulin signaling pathway and AMPK 8
Figure 2. Davallia formosana Hayata 10
Figure 3. Hypolepis punctata (Thunb.) Mett. 18
Figure 4. HR-ESI-MS of epiphyllocoumarin-3-O-β-D-allopyranoside (4) 33
Figure 5. 1H-NMR spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz) 34
Figure 6. Partialyl expanded 1H-NMR spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz, δ 6.0 - δ 8.0) 34
Figure 7. Partial expanded 1H-NMR spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz, δ 2.0 - δ 4.0) 35
Figure 8. BBD 13C-NMR spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 125 MHz) 35
Figure 9. HMQC spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz) 36
Figure 10. 1H-1H COSY spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz) 37
Figure 11. Partialyl expanded 1H-1H COSY spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz) 38
Figure 12. HMBC spectrum of epiphyllocoumarin-3-O-β-D-allopyranoside (4) (DMSO-d6, 500 MHz) 39
Figure 13. HR-ESI-MS of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) 44
Figure 14. 1H-NMR spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) (CD3OD, 500 MHz) 45
Figure 15. Partialyl expanded 1H-NMR spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-
allopyranoside (5) (CD3OD, 500 MHz, δ 5.0 - δ 7.0) 45
Figure 16. Partialyl expanded 1H-NMR spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-
allopyranoside (5) (CD3OD, 500 MHz, δ 2.0 - δ 5.0) 46
Figure 17. BBD 13C-NMR spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) (CD3OD, 125 MHz) 46
Figure 18. HMQC spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) (CD3OD, 500 MHz) 47
Figure 19. 1H-1H COSY spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) (CD3OD, 500 MHz) 48
Figure 20. HMBC spectrum of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D-allopyranoside (5) (CD3OD, 500 MHz) 49
Figure 21. HR-ESI-MS of (+)-3-O-caffeoyl-L-glyceric acid (22) 52
Figure 22. 1H-NMR spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 500 MHz) 53
Figure 23. Partialyl expanded 1H-NMR spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 500 MHz) 53
Figure 24. BBD 13C-NMR spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 125 MHz) 54
Figure 25. HMQC spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 500 MHz) 55
Figure 26. 1H-1H COSY spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 500 MHz) 56
Figure 27. HMBC spectrum of (+)-3-O-caffeoyl-L-glyceric acid (22) (CD3OD, 500 MHz) 57
Figure 28. HR-ESI-MS of (+)-3-O-p-coumaroyl-L-glyceric acid (23) 60
Figure 29. 1H-NMR spectrum of (+)-3-O-p-coumaroyl-L-glyceric acid (23) (CD3OD, 500 MHz) 61
Figure 30. BBD 13C-NMR spectrum of (+)-3-O-p-coumaroyl-L-glyceric acid (23) (CD3OD, 125 MHz) 61
Figure 31. HMQC spectrum of (+)-3-O-p-coumaroyl-L-glyceric acid (23) (CD3OD, 500 MHz) 62
Figure 32. 1H-1H COSY spectrum of (+)-3-O-p-coumaroyl-L-glyceric acid (23) (CD3OD, 500 MHz) 63
Figure 33. HMBC spectrum of (+)-3-O-p-coumaroyl-L-glyceric acid (23) (CD3OD, 500 MHz) 64
Figure 34. HR-ESI-MS of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β- D- glucopyranoside (38) 67
Figure 35. 1H-NMR spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β- D-glucopyranoside (38) (CD3OD, 500 MHz) 68
Figure 36. BBD 13C-NMR spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl- (1→6))-β-D-glucopyranoside (38) (CD3OD, 125MHz) 68
Figure 37. HMQC spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D-glucopyranoside (38) (CD3OD, 500 MHz) 69
Figure 38. 1H-1H COSY spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D -glucopyranoside (38) (CD3OD, 500 MHz) 70
Figure 39. Partialyl expanded 1H-1H COSY spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D-glucopyranoside (38) (CD3OD, 500 MHz) 71
Figure 40. HMBC spectrum of quercetin-3-O-(3-O-acetyl-α-L-rhamnopyranosyl-(1→6))-β-D-glucopyranoside (38) (CD3OD, 500 MHz) 72
Figure 41. The xanthine oxidase (XOD)-inhibitory activity of 2, 3 and 4 from D. formosana 75
Figure 42. The uric acid-lowering effects of compounds 2, 3, and 4 from D. formosana on mice with potassium oxonate (PTO)-induced hyperuricemia.. 75
Figure 43. Predicted binding mode of epiphyllocoumarin-3-O-β-D-allopyranoside (4) docked into the active site of xanthine oxidase.. 77
Figure 44. Effect of fraction DFH, DFE and DFB from D. formosana on RANKL-induced osteoclastogenesis. 79
Figure 45. Effect of compounds 1-20 from D. formosana on RANKL-induced osteoclastogenesis. 79
Figure 46. The isolation process of 1-20 from Davallia formosana Hayata 103
Figure 47. The isolation process of 21-43 from Hypolepis punctata (Thunb.) Mett. 106
Scheme 1. Acid hydrolysis of compound 4 31
Scheme 2. Alkaline hydrolysis of compound 22 50
Scheme 3. Mild Alkaline hydrolysis of compound 38 66
表目錄
Table 1. The general drugs used to treat gout and hyperuricemia 2
Table 2. The clinically used drugs to treat osteoporosis
5
Table 3. Known flavonoids from D. formosana and H. punctate.
25
Table 4. Known penolics from D. formosana and H. punctate.
27
Table 5 . Known triterpenoids compounds from D. formosana
28
Table 6. Known lignans from H. punctate. 28
Table 7. Known sesquiterpenoids from H. punctate 29
Table 8. 13C and 1H-NMR spectroscopic data of epiphyllocoumarin-3-O-β-D-allopyranoside (4) 32
Table 9. 13C and 1H-NMR spectroscopic data of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D- allopyranoside (5) 42
Table 10. 13C and 1H-NMR spectroscopic data of 8-(2-pyrrolidinone-5-yl)-catechin-3-O-β-D- allopyranoside (5) and Davallioside B 43
Table 11. 13C and 1H-NMR spectroscopic data of (+)-3-O-caffeoyl-L-glyceric acid (22) 51
Table 12. 13C and 1H-NMR spectroscopic data of (+)-3-O-p-coumaroyl-L-glyceric acid (23) and (+)-3-O-caffeoyl-L-glyceric acid (22) 59
Table 13. XOD-inhibitory activities of allopurinol and compounds 1-20 isolated from D. formosana 74
Table 14. Effect of compounds 21-43 from H. punctata on glucose uptake in rat L6 myocytes 81
Table 15. The yield of compounds 1-20 from Davallia formosana Hayata. 84
Table 16. The yield of compounds 21- 43 from Hypolepis punctata (Thunb.) Mett.. 93
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