臺灣博碩士論文加值系統

本研究利用抑制革蘭氏陽性金黃色葡萄球菌 (Staphylococcus aureus) 之活性為篩選平台，發現長沙枝菜 (Hypnea Charoides) 之衍生真菌株Aspergillus unguis NTU142的MY (malt extract, yeast extract) 醱酵培養液具顯著的抑菌活性。接著以MY (malt extract, yeast extract) 液態培養基加以擴大培養，針對其醱酵液所含代謝產物進行分析、分離與純化，共計獲得13個化合物，藉由各種光譜分析決定其結構。其中4個新化合物，包括：unguistin A (1)、unguistin B (2)、unguisine A (3) 和unguisine B (4)，另外為9個為已知化合物unguinol (5)、aspergillusidone A (6)、2-chlorounguinol (7)、aspergillusidone C (8)、agonodepside A (9)、7-chlorofolipastatin (10)、nornidulin (11)、pilobolusate (12) 和2,4-dichlorounguinol (13)。各化合物進行抑菌活性評估，得知agonodepside A (9) 和7-chlorofolipastatin (10) 對金黃色葡萄球菌 (Staphylococcus aureus) 與其他化合物相比有最佳的抑菌活性，其最小抑菌濃度 (MIC) 皆為4 μg/ml。在抑制 BV-2 細胞的生成一氧化氮上，aspergillusidone A (6) 有顯著的效果，其半抑制濃度 (IC50) 為 5.1 ± 1.6 μM。

Marine environment is one of the most important sources regarding natural product research. Besides, marine microorganisms have been denominated as talented natural sources for discovery of new leads. The target fungus, Aspergillus unguis NTU142, was isolated from a marine red alga Hypnea charoides, and was found to exhibit significant inhibitory activity against Staphylococcus aureus in our preliminary screening. Thus, a series of separation and purification of the active principles was undertaken. Thirteen compounds were isolated from large-scale fermentation broth of A. unguis NTU142, including four new unguistin A (1), unguistin B (2), unguisine A (3) and unguisine B (4), together with nine previously reported unguinol (5), aspergillusidone A (6), 2-chlorounguinol (7), aspergillusidone C (8), agonodepsides A (9), 7-chlorofolipastatin (10), nornidulin (11), pilobolusate (12) and 2,4-dichlorounguinol (13). Agonodepsides A (9) and 7-chlorofolipastatin (10) are likely responsible for the anti-microbial activity of the marine-derived A. unguis NTU142, which exhibited significant growth inhibition against S. aureus and C. neoformans. Aspergillusidone A (6) showed the most potent inhibitory effect on LPS-induced NO production in murine brain microglial BV-2 cells without cytotoxic activity.

目錄

誌謝 i
中文摘要 ii
ABSTRACT iii
目錄 v
圖目錄 viii
表目錄 xii
Chapter 1 前言 1
Chapter 2 文獻回顧 7
2.1 分類地位與介紹 7
2.2 Aspergillus屬真菌成份之文獻回顧 7
Chapter 3 實驗結果 26
3.1 Aspergillus unguis NTU142培養液分離流程 26
3.1.1 化合物 1-13 28
3.2 天然物結構分析 29
3.2.1 Unguistin A (1) 之結構解析 29
3.2.2 Unguistin B (2) 之結構解析 35
3.2.3 Unguisine A (3) 之結構解析 41
3.2.4 Unguisine B (4) 之結構解析 47
3.2.5 Unguinol (5) 之結構解析 54
3.2.6 Aspergillusidone A (6) 之結構解析 58
3.2.7 2-Chlorounguinol (7) 之結構解析 62
3.2.8 Aspergillusidone C (8) 之結構解析 66
3.2.9 Agonodepsides A (9) 之結構解析 70
3.2.10 7-Chlorofolipastatin (10) 之結構解析 73
3.2.11 Nornidulin (11) 之結構解析 76
3.2.12 Pilobolusate (12) 之結構解析 80
3.2.13 2,4-Dichlorounguinol (13) 之結構解析 83
3.3 各成分之物理數據 90
3.4 抑菌試驗 94
3.5 一氧化氮抑制試驗 96
Chapter 4 實驗方法 98
4.1 儀器設備與試劑 98
4.1.1 化合物物理性質測定儀器 98
4.1.2 高效能液態層析系統 98
4.1.3 低壓管住色層層析系統 98
4.1.4 試劑耗材與溶劑 98
4.1.5 真菌培養基 99
4.1.6 細菌培養基 99
4.2 材料 99
4.2.1 真菌材料 99
4.2.2 細菌材料 99
4.2.3 菌種鑑定 99
4.2.4 真菌篩選與萃取 100
4.3 抗菌活性初篩 100
4.3.1 目的 100
4.3.2 檢測原理 100
4.3.3 測試菌種 101
4.3.4 實驗步驟 101
4.4 真菌培養與成分分離 102
4.4.1 培養基製備 102
4.4.2 真菌發酵液萃取 103
4.4.3 粗萃物成分之分離與純化 103
4.5 一氧化氮之活性抑制試驗 105
4.5.1 細胞培養 106
4.5.2 Griess reagent assay 106
4.6 抗菌活性評估 107
4.6.1 檢測原理 107
4.6.2 測試菌種 107
4.6.3 Chequerboard titration assay 107
Chapter 5 討論 108
Chapter 6 參考文獻 110

圖目錄

Fig. 1.1數種藻源真菌對於白色念珠菌 (Candida albicans) 的抗菌活性初篩。A: NTU142, B: NTU139 2
Fig. 1.2 Aspergillus unguis NTU142由不同培養基醱酵粗萃物的抗菌活性。(PDY medium, MEA medium, YES medium, MY medium, 1/2 PDA medium, 1/2 PDY medium) 3
Fig. 1.3 1985─2012年海洋天然物之活性與非活性天然物數量統計。[107] 4
Fig. 1.4 1985─2012年海洋天然物之個別活性數量統計。[107] 4
Fig. 1.5 (A) 海洋麴黴天然物來源 (B) 海洋麴黴結構分類。[107] 5
Fig. 1.6主要結構類型化合物產生麴黴菌的棲息地。[107] 5
Fig. 1.7 (A) 海洋麴黴天然物的活性分類 (B) 海洋麴黴天然物中各結構類型比例。[107] 6
Fig. 1.8 (A) 不同結構類型化合物的活性比率 (B)不同來源化合物的活性比例。[107] 6
Fig. 3.1化合物1之高解析電灑游離質譜。 31
Fig. 3.2化合物1之紅外光譜。 31
Fig. 3.3化合物1之氫譜 (methanol-d4, 500MHz)。 32
Fig. 3.4化合物1之碳譜 (methanol-d4, 125MHz)。 32
Fig. 3.5化合物1之HSQC圖譜。 33
Fig. 3.6化合物1之COSY圖譜。 33
Fig. 3.7化合物1之HMBC圖譜。 34
Fig. 3.8化合物2之高解析電灑游離質譜。 37
Fig. 3.9化合物2之紅外光譜。 37
Fig. 3.10化合物2之氫譜 (methanol-d4, 500MHz)。 38
Fig. 3.11化合物2之碳譜 (methanol-d4, 125MHz)。 38
Fig. 3.12化合物2之HSQC圖譜。 39
Fig. 3.13化合物2之COSY圖譜。 39
Fig. 3.14化合物2之HMBC圖譜。 40
Fig. 3.15化合物3之高解析電灑游離質譜。 43
Fig. 3.16化合物3之紅外光譜。 43
Fig. 3.17化合物3之氫譜 (methanol-d4, 500MHz)。 44
Fig. 3.18化合物3之碳譜 (methanol-d4, 125MHz)。 44
Fig. 3.19化合物3之HSQC圖譜。 45
Fig. 3.20化合物3之HMBC圖譜。 45
Fig. 3.21化合物3之1D Selective NOESY圖譜之一。 46
Fig. 3.22化合物3之1D Selective NOESY圖譜之二。 46
Fig. 3.23化合物4之高解析電灑游離質譜。 49
Fig. 3.24化合物4之紅外光譜。 49
Fig. 3.25化合物4之氫譜 (methanol-d4, 500MHz)。 50
Fig. 3.26化合物4之碳譜 (methanol-d4, 125MHz)。 50
Fig. 3.27化合物4之HSQC圖譜。 51
Fig. 3.28化合物4之COSY圖譜。 51
Fig. 3.29化合物4之HMBC圖譜。 52
Fig. 3.30化合物4之1D Selective NOESY圖譜之一。 52
Fig. 3.31化合物4之1D Selective NOESY圖譜之二。 53
Fig. 3.32化合物5之高解析電灑游離質譜。 56
Fig. 3.33化合物5之紅外光譜。 56
Fig. 3.34化合物5之氫譜 (methanol-d4, 500MHz)。 57
Fig. 3.35化合物5之碳譜 (methanol-d4, 125MHz)。 57
Fig. 3.36化合物6之高解析電灑游離質譜。 60
Fig. 3.37化合物6之紅外光譜。 60
Fig. 3.38化合物6之氫譜 (methanol-d4, 500MHz)。 61
Fig. 3.39化合物6之碳譜 (methanol-d4, 125MHz)。 61
Fig. 3.40化合物7之高解析電灑游離質譜。 64
Fig. 3.41化合物7之紅外光譜。 64
Fig. 3.42化合物7之氫譜 (methanol-d4, 500MHz)。 65
Fig. 3.43化合物7之碳譜 (methanol-d4, 125MHz)。 65
Fig. 3.44化合物8之高解析電灑游離質譜。 68
Fig. 3.45化合物8之紅外光譜。 68
Fig. 3.46化合物8之氫譜 (methanol-d4, 500MHz)。 69
Fig. 3.47化合物8之碳譜 (methanol-d4, 125MHz)。 69
Fig. 3.48化合物9之高解析電灑游離質譜。 71
Fig. 3.49化合物9之紅外光譜。 71
Fig. 3.50化合物9之氫譜 (methanol-d4, 400MHz)。 72
Fig. 3.51化合物10之高解析電灑游離質譜。 74
Fig. 3.52化合物10之紅外光譜。 74
Fig. 3.53化合物10之氫譜 (methanol-d4, 400MHz)。 75
Fig. 3.54化合物11之高解析電灑游離質譜。 78
Fig. 3.55化合物11之紅外光譜。 78
Fig. 3.56化合物11之氫譜 (methanol-d4, 500MHz)。 79
Fig. 3.57化合物11之碳譜 (methanol-d4, 125MHz)。 79
Fig. 3.58化合物12之高解析電灑游離質譜。 81
Fig. 3.59化合物12之紅外光譜。 81
Fig. 3.60化合物12之氫譜 (methanol-d4, 400MHz)。 82
Fig. 3.61化合物13之高解析電灑游離質譜。 84
Fig. 3.62化合物13之紅外光譜。 84
Fig. 3.63化合物13之氫譜 (methanol-d4, 400MHz)。 85
Fig. 3.64化合物在20 M 下，抑制 BV-2 細胞一氧化氮的產生。R = Resting, V = Vehicle (+LPS) 97
Fig. 3.65化合物對於 BV-2 細胞之存活率影響。R = Resting 97
Fig. 4.1 紙錠擴散法 (disk-diffusion method) 實驗流程示意圖。 102

表目錄

Table 1海洋麴黴屬具細胞毒性之成分 8
Table 2海洋麴黴屬具抑菌之成分 12
Table 3海洋麴黴屬具自由基清除之成分 15
Table 4海洋麴黴屬具抗寄生蟲之成分 16
Table 5化合物1─4氫譜數據。 86
Table 6化合物5─13氫譜數據。 87
Table 7化合物1─4碳譜數據 88
Table 8化合物5─8, 11碳譜數據 89
Table 9化合物1─13之最低抑菌濃度和最低殺菌濃度 95
Table 10三株實驗病原菌編號以及培養條件 95

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