臺灣博碩士論文加值系統

摘要
近年來海洋生物被認為是最有潛力開發新藥物的來源，其中由軟珊瑚發現許多具有活性的二次代謝物，為了從台灣海域的軟珊瑚開發出新的藥物。本論文針對四種軟珊瑚Cespitularia taeniata、 Clavularia viridis、 Sinularia flexibilis與Asterospicularia laurae的有機層萃取物來尋找活性物質。並分析鑑定其所含的化學成分，共計分離得到五十七個天然化合物，其中有二十九個為新化合物，並檢測分離得到的化合物的生物活性。
由軟珊瑚Cespitularia taeniat中分離出三個含氮的新天然物，將其命名為cespitulactams A (1)、B (2)和C (3).此三個新穎的化合物為在C-10位有苯胺基丙酸(phenylethyl amino acid)取代和C-20位接有醯胺的官能基，並將其做化學結構修飾，探討其結構與活性之間的關係。在細胞毒殺活性方面，發現 cespitulactam A (1)對兩種癌細胞 WiDr (人類結腸腺癌) 和 Daoy (人類神經管母細胞瘤)具有抗癌活性，其IC50值分別為2.72 和6.34 μg/ml。
從軟珊瑚Clavularia viridis中分離得到八個天然化合物，其中包括五個新的類前列腺素化合物，並命名為 claviridic acids A–E (6–11)，以及三個已知的化合物clavulones I–III (35-37)。在生物活性方面發現這些分離得到的類前列腺素化合物對於因PHA所引起的PBMC 細胞增生存有顯著的抑制作用。而在細胞毒殺活性測試中發現亦對AGS (人類胃癌細胞)具有顯著的毒殺活性。
在台灣南部海岸產的軟珊瑚 Sinularia flexibilis 的研究中，分離得到十個新的化合物並命名為flexilarins A-J (12–21)，以及十七個已知的化合5-dehydrosinulariolide(49)、(1R,13S,12S,9S,8R,5S,4R)-9-acetoxy-5,8,12,13-
diepoxycembr-15(17)-en-16,4-olide(45) 、 sinulariolone (54) 、 dihydrosinuflexolide (38) 、 sinularin (39) 、, dihydrosinularin (40) 、14-deoxycrassin (42) 、sinuflexolide (41) 、sinulaflexiolide E (43) 、 sinuflexibilin (44) 、 sinulariolide (47) 、 11-sinulariolide acetate (48) 、 capilloloid (50) 、 7-hydro-cembranolide (46) 、sandensolide (51) 、querciformolide B (52) and querciformolide D (53)。在細胞毒殺活性上，顯示flexilarin D (15)對於Hep2 (人類咽喉癌細胞)有顯著的細胞毒殺活性。
在軟珊瑚Asterospicularia laurae中，分離得到十一個Xenicanes類的新化合物Asterospicularins A-K (22-32)，以及六個已知化合物 xeniolide-B 9-acetate (55)、 xeniolide A (56) 、 7,8- epoxy -isoxeniolid A (57) 、 xenialactol (58) 、 sinularin (59) 、 dihydrosinularin (60)。
有關這些新化合物的結構解析是利用一維與二維核磁共振光譜與各種物理性質(包括旋光、紫外光譜、紅外光譜、CD光譜、質譜)配合比對相關文獻來決定。
此外，flexilarin A (12)和5-dehydrosinulariolide (49)的化學結構是經由X-ray單晶繞射解析所證明。

Abstract
The marine organisms are considered to a valuable source for developing new medicine in recent years. Among them, a lot of secondary metabolites were found with interesting biological activities in the soft coral. In order to develop new medicine from the soft corals in coastal waters off area of Taiwan. We have established the dissertation for the study of bioactive metabolites from the organic extracts of four soft corals including Cespitularia taeniata, Clavularia viridis, Sinularia flexibilis and Asterospicularia laurae. Fifty-seven compounds, including twenty nine new natural products were isolated and parts of their biological activities were investigated.
Three new nitrogen-containing diterpenoids, designated cespitulactams A (1), B (2), and C (3) were isolated from Cespitularia taeniata May. Compounds 1–3 are novel structures having a phenylethyl amino side chain at C-10 and with an amide function at C-20. Some compounds were modified for structure- activity relationships studies. Compound 1 exhibited significant cytotoxicity against human Widr (human colon adenocarcinoma) and Daoy (human medulloblastoma) cancer cells at IC50 2.72 and 6.34 μg/ml.
Investigation of the soft coral Clavularia viridis found eight prostanoids, including five new prostanoids, designated as claviridic acids A–E (6–11), together with three known prostanoids, clavulones I–III (35-37). The isolated marine prostanoids exhibited potent inhibitory effect on PHA-induced proliferation of peripheral blood mononuclear cells (PBMC), as well as significant cytotoxic activity against human gastric cancer cells (AGS).
Chemical investigation of the soft coral Sinularia flexibilis, collected from the southern coast off Taiwan, leading to the isolation of ten new flexilarins A-J (12–21), along with seventeen known compounds, 5-dehydrosinulariolide (49), (1R,13S,12S,9S,8R,5S,4R)-9-acetoxy- 5,8, 12,13-diepoxycembr-15(17)-en-16,4-olide (45), sinulariolone (54), dihydrosinuflexolide (38), sinularin (39), dihydrosinularin (40), 14-deoxycrassin (42), sinuflexolide (41), sinulaflexiolide E (43), sinuflexibilin (44), sinulariolide (47), 11-sinulariolide acetate (48), capilloloid (50), 7-hydro-cembranolide (46), sandensolide (51), querciformolide B (52). Flexilarin D (15) exhibited potent cytotoxicity against Hep2 (human laryngeal carcinoma) tumor cells.
The investigation of Asterospicularia laurae obtained eleven xenicanes-type compounds Asterospicularin A-K (22-32), and six known xeniolide-B 9-acetate (55), xeniolide A (56), 7,8- epoxy -isoxeniolid A (57), xenialactol (58), sinularin (59) and dihydrosinularin (60).
The structures of new compounds were determined by 1D and 2D-NMR spectroscopic analysis and physical methods such as optical rotation, UV, IR, CD, mass spectrum, as well as comparison with the spectroscopic data of reported compounds. Moreover, the structure of flexilarin A (12) and 5-dehydrosinulariolide (49) were confirmed by X-ray crystallographic analysis.

目錄
Page
摘要
第一部份、緒論
第一章 前言 1
第二章 研究動機與展望 3
第三章 相關化合物之研究與文獻回顧
第一節 Cespitularia taeniata 屬 5
第二節 Clavularia viridis 屬 14
第三節 Sinularia flexibilis 屬 26
第四節 Asterospicularia laurae 屬 47
第二部份、材料與方法
第一章 樣品的採集與分類地位
第一節 Cespitularia taeniata 屬 49
第二節 Clavularia viridis 屬 50
第三節 Sinularia flexibilis 屬 51
第四節 Asterospicularia laurae 屬 52
第二章 分離與純化
第一節 Cespitularia taeniata 屬 53
第二節 Clavularia viridis 屬 55
第三節 Sinularia flexibilis 屬 58
第四節 Asterospicularia laurae 屬 64
第三章 結構之鑑定
第一節 儀器 69
第二節 矽膠與溶劑 70
第三部份、結果與討論
第一章 Cespitularia taeniata 屬
Cespitulactam A (1)之結構解析 72
Cespitulactam B (2)之結構解析 80
Cespitulactam C (3)之結構解析 86
Cespitulactam A monoacetate (4)之結構解析 92
Cespitulactam C monoacetate (5)之結構解析 96
第二章 Clavularia viridis 屬
Claviridic acid A (6)之結構解析 100
Claviridic acid B (7)之結構解析 108
Claviridic acid B monoacetate (8)之結構解析 115
Claviridic acid C (9)之結構解析 119
Claviridic acid D (10)之結構解析 126
Claviridic acid E (11)之結構解析 133
第三章 Sinularia flexibilis 屬
Flexilarin A (12)之結構解析 141
Flexilarin B (13)之結構解析 148
Flexilarin C (14)之結構解析 156
Flexilarin D (15)之結構解析 163
Flexilarin E (16)之結構解析 169
Flexilarin F (17)之結構解析 176
Flexilarin G (18)之結構解析 183
Flexilarin H (19)之結構解析 190
Flexilarin I (20)之結構解析 197
Flexilarin J (21)之結構解析 205
第四章 Asterospicularia laurae 屬
Asterospicularin A (22)之結構解析 212
Asterospicularin B (23)之結構解析 220
Asterospicularin C (24)之結構解析 227
Asterospicularin D (25)之結構解析 235
Asterospicularin E (26)之結構解析 242
Asterospicularin F (27)之結構解析 249
Asterospicularin G (28)之結構解析 257
Asterospicularin H (29)之結構解析 265
Asterospicularin I (30)之結構解析 273
Asterospicularin J (31)之結構解析 280
Asterospicularin K (32)之結構解析 287
第五章 活性測試結果
第一節 Cespitularia taeniata 屬 294
第二節 Clavularia viridis 屬 295
第三節 Sinularia flexibilis 屬 298
第四部份、結論 300
第五部份、參考文獻 304

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