摘要
隔板葉形軟珊瑚Lobophytum crassum，是亞太地區珊瑚礁中常見的珊瑚之一，其含有豐富的固醇類與萜類化合物，尤其是cembrane-type 的二萜類化合物，本實驗從養殖型L. crassum 的乙酸乙酯萃取物中分離得到14個化合物，包含一個新α-tocopherol類化合物 crassumtocopherol C (1)，一個新cembranoid類化合物 culobophylin D (2)與一個新天然化合物 pseudoplexauric acid (3)以及11個已知化合物 cembrene (4)、lobophylin B (5)、crassocolide E (6) 、sarcocrassocolide (7) 、13-acetoxysarcocrassocolide (8) 、14-deoxycrassin (9)、lobocrassins B (10)和C (11)、sarcocrassocolides F (12), G (13) 和 M (14)。化合物1−14化學結構經由光譜數據分析及比對相關文獻資料而確認。
在生物活性方面，化合物5−8分別對6種癌細胞 K562、Molt-4、U937、Sup-T1、Ca9-22和Lncap進行細胞毒殺試驗，結果顯示化合物8對上述的6種細胞株皆具有良好的細胞毒殺活性 (IC50 =1.24、0.46、2.47、0.56、1.19和6.68 μg/mL)，化合物6、7對 K562、Molt-4、U937、Sup-T1和Ca9-22五種細胞株具有良好的細胞毒殺活性 (IC50 =3.57、1.95、4.99、1.64和4.24; 5.73、2.66、1.38、2.63和8.63 μg/mL)。此外化合物9−14分別對4種血癌細胞株K562、Molt-4、U937和Sup-T1進行細胞毒殺試驗，結果顯示化合物9、10、12−14對上述4種血癌細胞皆具有良好的細胞活性。由細胞毒殺實驗結果可以推測化合物6−10、12−14 cembranoid類雙萜化合物的 C-1上α−methylene−γ−lactonec或是α−methylene−δ−lactone部位可能是細胞毒殺的主要功能性之片段結構。

Abstract
Lobophytum crassum, the alcyonacean coral, is one of the most common corals in reef flat communities in Asia-Pacific region. They are rich in steroids and terpenoids especially cembranoid diterpenes. We isolated fourteen compounds from the ethyl acetate extract of the cultured L. crassum. The isolated compounds included: a new α-tocopherol, crassumtocopherol C (1); a new cembranoid, culobophylin D (2); and a new natural product, pseudoplexauric acid (3), along with eleven known compounds, cembrene (4), lobophylin B (5), crassocolide E (6), sarcocrassocolide (7), 13-acetoxysarcocrassocolide (8), 14-deoxycrassin (9), lobocrassins B (10) and C (11), sarcocrassocolides F (12), G (13) and M (14).The structures of the isolates were elucidated using several spectroscopic techniques and by comparison of their spectroscopic data with those of the related metabolites.
The cytotoxic activity of 5−8 was evaluated against six cancer cell lines including K562, Molt-4, U937, Sup-T1, Ca9-22 and Lncap. Compound 8 exhibited the most potent cytotoxic activity against the tested six cancer cell lines (IC50 =1.24, 0.46, 2.47, 0.56, 1.19, 6.68 μg/mL), and 6−7 showed cytotoxicity against K562, Molt-4, U937, Sup-T1, Ca9-22 cancer cell lines (IC50 =3.57, 1.95, 4.99, 1.64, 4.24; 5.73, 2.66, 1.38, 2.63, 8.63 μg/mL). Moreover, the cytotoxic activity of 9−14 was evaluated against leukemia cell lines K562, Molt-4, U937, and Sup-T1. Compounds 9, 10, and 12−14 exhibited significant cytotoxicity against these leukemic cancer cell lines. Based on these results, it is suggested that the α−methylene−γ−lactone or α−methylene−δ−lactone moiety attached to C-1 in compounds 6−10 and 12−14 is critical for the cytotoxicity activity of these cembranoid diterpenes.

目錄
第一章、緒論 1
第一節、前言 1
第二節、文獻回顧 5
第二章、生物材料與研究方法 53
第一節、生物樣品採集與分類 53
第二節、生物樣品的萃取分離 55
第三節、實驗器材與材料 57
第三章、結果與討論 59
第一節、Lobophytum crassum 所含化合物之結構解析 59
(一)、Crassumtocopherol C (1) 之結構解析 61
(二)、Culobophylin D (2) 之結構解析 71
(三)、Pseudoplexauric acid (3) 之結構解析 81
(四)、Cembrene (4) 之結構解析 91
(五)、Lobophylin B (5) 之結構解析 97
(六)、Crassocolide E (6) 之結構解析 101
(七)、Sarcocrassocolide (7) 之結構解析 105
(八)、13-Acetoxysarcocrassocolide (8) 之結構解析 109
(九)、14-Deoxycrassin (9) 之結構解析 113
(十)、Lobocrassin B (10) 之結構解析 115
(十一)、Lobocrassin C (11) 之結構解析 119
(十二)、Sarcocrassocolide F (12) 之結構解析 123
(十三)、Sarcocrassocolide G (13) 之結構解析 127
(十四)、Sarcocrassocolide M(14) 之結構解析 131
第二節、新化合物實驗數據整理 135
第四章、生物活性試驗 137
第一節、細胞毒殺試驗 137
(一)、細胞培養 (Cell culture) 137
(二)、細胞冷凍保存 138
(三)、冷凍細胞活化 138
(四)、細胞毒殺活性試驗 (MTT assay) 138
(五)、Annexin V/ PI 雙重染色檢測細胞凋亡之程度 139
(六)、檢測細胞內粒線體膜電位之變化 139
第二節、生物活性試驗結果 141
(一)、細胞毒殺活性試驗結果 141
(二)、14-Deoxycrassin (9) Lobocrassin B (10)誘導Leukemia
cell 凋亡 142
第五章、結論 147
第六章、參考文獻 149

圖目錄
Figure 1-1. 海洋天然物及衍生物臨床用藥及其結構. 3
Figure 1-2. 2006−2011年各國發表新海洋天然物數量變化圖 4
Figure 2-1. Lobophytum crassum 隔板葉形軟珊瑚生態照I 54
Figure 2-2. Lobophytum crassum 隔板葉形軟珊瑚生態照II. 54
Figure 2-3. Lobophytum crassum分離流程. 56
Figure 3-1-1. The 1H-1H COSY and selected HMBC correlations for 1 62
Figure 3-1-2. Crassumtocopherol C相對立體結構 63
Figure 3-1-3. Crassumtocopherol A相對立體結構 63
Figure 3-1-4. 化合物 1 之低解析度ESIMS圖譜 65
Figure 3-1-5. 化合物 1 之高解析度ESIMS圖譜 65
Figure 3-1-6. 化合物 1 之IR圖譜 66
Figure 3-1-7. 化合物 1 之1H-NMR圖譜 66
Figure 3-1-8. 化合物 1 之1H-NMR放大圖譜 67
Figure 3-1-9. 化合物 1 之1H-NMR放大圖譜 67
Figure 3-1-10. 化合物 1 之13C-NMR圖譜 68
Figure 3-1-11. 化合物 1 之DEPT圖譜 68
Figure 3-1-12. 化合物 1 之HSQC圖譜 69
Figure 3-1-13. 化合物 1 之HMBC圖譜 69
Figure 3-1-14. 化合物 1 之COSY 圖譜 70
Figure 3-1-15. 化合物 1 之NOESY 圖譜 70
Figure 3-2-1. Selected 1H-1H COSY and HMBC correlations for 2 72
Figure 3-2-2. Selected NOESY correlation of 2 73
Figure 3-2-3. 化合物 2 之低解析度ESIMS圖譜 75
Figure 3-2-4. 化合物 2 之高解析度ESIMS圖譜 75
Figure 3-2-5. 化合物 2 之IR圖譜 76
Figure 3-2-6. 化合物 2 之1H-NMR圖譜 76
Figure 3-2-7. 化合物 2 之1H-NMR放大圖譜 77
Figure 3-2-8. 化合物 2 之1H-NMR放大圖譜 77
Figure 3-2-9. 化合物 2 之13C-NMR圖譜 79
Figure 3-2-10. 化合物 2 之DEPT圖譜 79
Figure 3-2-11. 化合物 2 之HSQC圖譜 80
Figure 3-2-12. 化合物 2 之HMBC圖譜 80
Figure 3-2-13. 化合物 2 之COSY 圖譜 81
Figure 3-2-14. 化合物 2 之NOESY 圖譜 81
Figure 3-3-1. 化合物 3 之低解析度ESIMS圖譜 83
Figure 3-3-2. 化合物 3 之高解析度ESIMS圖譜 83
Figure 3-3-3. 化合物 3 之IR圖譜 84
Figure 3-3-4. 化合物 3 之400 MHz 1H-NMR圖譜 84
Figure 3-3-5. 化合物 3 之500 MHz 1H-NMR圖譜 85
Figure 3-3-6. 化合物 3 之500 MHz 1H-NMR放大圖譜 85
Figure 3-3-7. 化合物 3 之500 MHz 1H-NMR放大圖譜 86
Figure 3-3-8. 化合物 3 之13C-NMR圖譜 86
Figure 3-3-9. 化合物 3 之DEPT圖譜 87
Figure 3-3-10. 化合物 3 之HSQC圖譜 87
Figure 3-3-11. 化合物 3 之HMBC圖譜 88
Figure 3-3-12 化合物 3 之COSY 圖譜 88
Figure 3-3-13 化合物 3 之NOESY 圖譜 89
Figure 3-4-1. 化合物 4 之1H-NMR圖譜 93
Figure 3-4-2. 化合物 4 之13C-NMR圖譜 93
Figure 3-4-3. 化合物 4 之DEPT圖譜 94
Figure 3-4-4. 化合物 4 之HSQC圖譜 94
Figure 3-4-5. 化合物 4 之HMBC圖譜 95
Figure 3-4-6. 化合物 4 之COSY圖譜 95
Figure 3-4-7. 化合物 4 之NOESY圖譜 96

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