臺灣博碩士論文加值系統

牛樟芝(Antrodia cinnamomea)為多孔菌科薄孔菌屬的寄生性真菌，是台灣特有的菌菇，具有抗癌、肝臟保護及免疫調節等功能。台灣民間常用牛樟芝來治療肝癌、肺癌及乳癌等，但相關的研究及作用機制仍有許多不清楚之處。本研究在分離純化牛樟芝的純化合物，並進一步探討其純化合物對於人類癌細胞的毒殺作用及機轉。
首先，將牛樟芝菌絲體以95%乙醇重複冷浸萃取後，以減壓濃縮後得乙醇層(ANCA-E)，再將乙醇層以二氯甲烷與水分配萃取後，得二氯甲烷層(ANCA-E-D)、水層(ANCA-E-W)共兩層；並針對人類癌細胞進行細胞毒殺活性試驗，依據牛樟芝粗萃取物之抗癌活性篩選結果，選取效果較佳之二氯甲烷層以矽膠柱層析法分離，經過二氯甲烷/甲醇當移動相梯度沖提分離，共得ANCA-E-D-1~4等四分層；再依據ANCA-E-D-1~4之抗癌活性篩選結果，選取效果較佳之ANCA-E-D-2~3使用製備型高壓液相管柱層析RP-8，以90% MeOH：H2O為移動相進行分離純化，共得到十三個化合物，其中十個為泛醌類(ubiquinones)化合物：antrocamol LT1 (1)、antrocamol LT2 (2)、antrocamol LT3 (3)、4-acetylantrocamol LT3 (4)、antroquinonol (5)、4-acetylantroquinonol (6)、antroquinonol B (7)、4-acetylantroquinonol B (8)、quinone Q3 (9)、antrocinnamone (10)，兩個為苯類(benzenoids)化合物：4,7-dimethoxy-5-methyl-1,3-benzodioxole (11)、2,4-dimethoxy-6-methyl-benzene-1,3-diol (12)，ㄧ個為丁烯二酸類(maleic acid)化合物：antrodin A (13)。上述成分中，化合物(1)、(2)、(3)、(4)、(10)為新化合物並首次由牛樟芝中分離得到。
根據純化合物對人類癌細胞毒殺效果，分析活性與化合物結構間是否具有關聯，結果發現泛醌類化合物對人類癌細胞IC50大約介於0.001 和 35.883 M之間，特別是具有4-hydroxy-cyclohex-2-enone及侧鏈具羥基的化合物對於癌細胞的毒殺效果較佳；進一步取牛樟芝新化合物4-acetylantrocamol LT3 (4)對HepG2肝癌細胞以流式細胞儀進行細胞週期影響分析，數據表明4-acetylantrocamol LT3 (4)對細胞週期 sub G1期阻滯可能會導致細胞凋亡。

Antrodia cinnamomea, belonging to the Polyporaceae family, is a parasitic fungus exhibited anti-cancer, hepatoprotective and immunomodulatory activities in Taiwan. A. cinnamomea was historically used in Taiwan by the aborigines as a traditional prescription against liver cancer、lung cancer and breast cancer, but the mechanisms were not very clear. In this study, we tried to isolate and purify new pure compounds from A. cinnamomea and further investigated the cytotoxic activities and mechanisms of pure compounds on human cancer cells.
The dried A. cinnamomea mycelium was extracted with 95% alcohol, and the extract was successively partitioned with dichloromethane and water. The dichloromethane-soluble fraction was subjected to column chromatography and HPLC separation. This procedure afforded thirdteen compounds 1–13. In all five new ubiquinones, antrocamol LT1 (1)、antrocamol LT2 (2)、antrocamol LT3 (3)、4-acetylantrocamol LT3 (4) and antrocinnamone (10), together with nine known compounds, including five known ubiquinones, antroquinonol (5)、4-acetylantroquinonol (6)、antroquinonol B (7)、4-acetylantroquinonol B (8) and quinone Q3 (9), two benzenoids, 4,7-dimethoxy-5-methyl-1,3-benzodioxole (11) and 2,4-dimethoxy-6-methyl-benzene-1,3-diol (12), and one maleic acid derivative, antrodin A (13), were identified by comparing their spectral data with literature values.
The cytotoxic activity of ubiquinones(compounds 1–10) exhibited potential and selective characteristics against three human cancer cell lines, A549, HepG2, and PC3, with IC50 values ranging from 0.001 to 35.883 M. We found that different cytotoxicity levels were related to their chemical structures, especially 4-hydroxy-cyclohex-2-enone ring and the presences of a free hydroxyl group in the side chain, could potentiate anticancer activity on three human cancer cells, A549, HepG2, and PC3. We suggest that the different cytotoxicity levels were related to their chemical structures, especially the 4-hydroxycyclohex-2-enone ring and the presence of a free hydroxyl group in the side chain. The suppression by 4-acetylantrocamol LT3 stopped the cell cycle at the beginning of the G2-M phase thus making the cell cycle arrest at the sub-G1 phase as compared with control cells. The sub-G1 phase accumulation could induce apoptosis subsequently.

第一章 緒論 1
第一節 癌症之定義及盛行率 1
第二節 肺癌現況 2
第三節 前列腺癌現況 5
第四節 肝癌現況 8
第五節 研究動機 10
第二章 牛樟芝介紹 14
第一節 藥材概述 14
第二節 化學成分回顧 19
第三節 化學成分結構式回顧 24
第四節 藥理活性回顧 32
第五節 牛樟芝之新藥研發 40
第六節 牛樟芝專利檢索 45
第三章 化學成分抽取與分離 56
第一節 抽取分層方法 56
第二節 化學成分之分離與纯化方法 57
第四章 化合物之結構鑑定 60
第一節 Antrocamol LT1 (1)之結構鑑定 60
第二節 Antrocamol LT2 (2)之結構鑑定 65
第三節 Antrocamol LT3 (3)之結構鑑定 68
第四節 4-Acetylantrocamol LT3 (4)之結構鑑定 71
第五節 Antrocinnamone (10)之結構鑑定 74
第六節 Antroquinonol (5)之結構鑑定 77
第七節 4-Acetylantroquinonol (6)之結構鑑定 80
第八節 牛樟芝純化合物HPLC圖譜 83
第五章 藥理活性試驗 84
第一節 藥理活性試驗介紹 84
第二節 牛樟芝粗抽物部分分層對人類癌細胞試驗結果 85
第三節 牛樟芝純化合物對人類癌細胞試驗結果 87
第四節 牛樟芝純化合物對細胞週期影響結果 91
第六章 實驗方法 93
第一節 材料與儀器 93
第二節 抽取與萃取 97
第三節 分離與純化 98
第四節 HPLC分析條件 100
第五節 細胞實驗方法 101
第七章 結論 108
參考文獻 110
純化合物之物理及光譜數據 118

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