臺灣博碩士論文加值系統

腸病毒71型 (Enterovirus 71, EV71) 於1969年美國加州首度分離出後，就一直在世界各地造成流行，其中以亞洲地區最為嚴重。1998年，台灣爆發了EV71大規模流行，超過一百五十萬人受感染，造成78個人死亡。不幸地，目前在臨床上並沒有有效的藥物或疫苗可以使用。在我們先前的相關研究顯示，薜荔具有良好抗腸病毒71型的活性，並由其95%乙醇萃取物分離出一活性成分—補骨脂酚 (Bakuchiol)。因此，本研究接續先前之研究，探討薜荔區分物抗腸病毒71型之活性成分。
首先，薜荔95%乙醇萃取物以 Amberlite XAD-7HP 分離得到11個活性區分 (IC50 = 4.6±0.1~ >160 μg/mL)，其中區分 G的總活性 (Total activity =454 mL) 為最高，區分 J則具有最低的IC50 (4.6±0.1μg/mL)。接著區分 G 以 Sephadex LH-20管柱層析分離得到G-I~G-Ⅸ 等9個區分，其中區分 G-V 有最低的IC50 (10±0.1 μg/mL)；區分G-V進行第一次矽膠管柱層析得到G-V-1~G-V-8等8個區分物，區分G-V-4有最低的IC50 ( 23.6±1.2 μg/mL)；區分 G-V-4再以第二次矽膠管柱層析分離得到G-V-4-1~G-V-4-4等4個區分 (IC50 = 12.6±2.3~65.9±4.3 μg/mL)。區分 J 經第一次半製備型C18-HPLC層析得到J-1~J-3等3個區分 (IC50 = 6.4±0.4~20.0±0.0 μg/mL)，區分 J-2再以第二次製備型C18-HPLC層析區分 J-2-3 (IC50 = 0.8±0.2 μg/mL)。其中之區分 G-V-4-1、G-V-4-2及J-2-3經由紫外光/可見光光譜儀、核磁共振光譜儀、液相串聯質譜儀及高解析質譜儀等圖譜之結果分別判斷為 Hexenyl isobutyl terephthlate、n-butyl isobutyl terephthalate 及 Tanshinone IIA。此3個化合物首次由薜荔被分離出來且首度報導具有抗EV71活性。丹參酮 IIA及補骨酯酚對EV71之抑制機轉包括預防病毒感染、直接殺死病毒、抑制病毒吸附宿主細胞及抑制病毒複製等作用，隨處理劑量增加，病毒抑制率也顯著上升 (p < 0.05)，而呈現劑量依賴型抑制效果。

Since first isolated in California, USA in 1969, the epidemics of enterovirus 71 (EV71) have circulated worldwide, especially in Asia. In 1998, a large outbreak of EV71 occurred and more than 1.5 million cases were infected including 78 deaths. Unfortunately, so far, there are still no effective drugs or vaccines for clinical therapy. In our previous study, 95% ethanol extract of Ficus pumila L. exhibited significant anti-EV71 activity and an active compound named bakuchiol was isolated. Hence, following previous study, the purpose of my study was to isolate the active ingredients from fractions of Ficus pumila L. on anti-EV71 activity.
95% ethanol extract of Ficus pumila L. was firstly subjected to Amberlite XAD-7HP column chromatography to obtain eleven active fractions (Frs A~L；IC50=4.6±0.1~ >160 μg/mL). Among all fractions, the Fr. G showed the highest total activity (454 mL) and Fr. J showed the lowest IC50 (4.6±0.1μg/mL). Fr. G was further chromatographed on a Sephadex LH-20 column to obtain nine fractions (Frs. G-I~Ⅸ) and Fr. G-V showed the lowest IC50 (10±0.1 μg/mL) within these fractions. Fr G-V was purified by chromatography over silica gel column to yield eight fractions (Frs. G-V-1~8). Fr. G-V-4 had showed the lowest IC50 (23.6±1.2 μg/mL) within these fractions and was further purified by chromatography over silica gel column to yield four fractions (Frs. G-V-4-1~4；IC50 = 12.6±2.3~65.9±4.3 μg/mL). Fr J was separated by semi-preparative C18-HPLC to obtain three fractions (Frs. J-1~J-3；IC50 = 20.0±0.0~6.4±0.4 μg/mL) and Fr. J-2 was further separated by semi-preparative C18-HPLC to obtain Fr. J-2-3 (IC50 = 0.8±0.2 μg/mL). Hexenyl isobutyl terephthalate, n-butyl isobutyl terephthalate and tanshinone II were identified in Fr. G-V-4-1, G-V-4-2 and J-2-3, respectively Three anti-EV71 active compounds were first isolated and reported in Ficus pumila L. . Time-of-addition assay demonstrated the anti-EV71 mechanisms of Tanshinone IIA and Bakuchiol including the prevention of viral infection, inactivating virus and inhibition of EV71 replication.

中文摘要 i
Abstract ii
縮寫表 iii
表目次 vi
圖目次 vii
壹、 前言 1
貳、 文獻整理 2
一、 腸病毒 2
(一) 腸病毒之概觀 2
(二) 腸病毒71型簡介 2
(三) 腸病毒71型之臨床症狀 7
(四) 腸病毒71型之流行病學 10
(五) 抗腸病毒71型藥物及其機轉 17
二、 薜荔 21
(一) 薜荔之基本介紹及傳統療效 21
(二) 薜荔之化學成分研究 22
(三) 薜荔之生理活性研究 22
參、 研究目的 28
肆、 研究架構 29
伍、 材料與方法 30
一、 實驗儀器 30
二、 實驗方法 30
(一) 樣品來源及製備 30
(二) 細胞株及病毒 31
(三) 細胞培養 32
(四) 病毒增殖及效價測定 33
(五) 50%細胞毒性濃度 34
(六) 50%抑制濃度測定 36
(七) 病毒感染時間點效應 38
(八) 分離純化 40
(九) 化學結構鑑定 43
陸、 結果與討論 46
一、 薜荔抗 EV71活性成分之分離 46
(一) Amberlite XAD-7HP 管柱層析 46
(二) Sephadex LH20 管柱層析 50
(三) 矽膠管柱層析 50
(四) 半製備型C18-HPLC 層析 54
二、 化學結構鑑定 57
(一) 區分 G-V-4-1 57
(二) 區分 G-V-4-2 57
(三) 區分 G-V-4-3 65
(四) 區分 G-V-4-4 71
(五) 區分 J-2-3 71
三、 丹參酮IIA及補骨酯酚時間點效應分析 76
(一) 丹參酮 IIA 82
(二) 補骨酯酚 82
四、 抗EV71活性成分之文獻探討 85
(一) Hexenyl isobutyl terephthalate 及 n-butyl isobutyl terephthalate之活性探討 85
(二) 丹參酮 ⅡA 之活性探討 87
柒、 結論 92
捌、 參考文獻 93

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