臺灣博碩士論文加值系統

第一部分：我們合成了具有代表性的天然物結構所衍生出的2-苯乙烯色素母酮衍生物，利用了簡單的合成方法來合成，並作為新型抗癌試劑的模板，以測試其細胞毒殺性(cytotoxicity)及作用機轉。經由生物活性的試驗後證實化合物38可抑制子宮頸癌細胞(HeLa Cell)生長並誘導細胞凋亡(apoptosis)，IC50值可達到4.9 μM。
第二部份：我們利用Mannich類型反應設計出8-羥基喹啉衍生物，並藉由修飾化合物90來合成出一系列8-羥基喹啉衍生物，來研究其分子結構與抗癌活性的關係(Structure-Activity Relationship)。經由生物活性的測試後證實可抑制一系列的癌細胞株生長。而最具抑制生長活性的化合物115，IC50值可達到0.7 μM。

The first part : A series of 2-styrylchromone analogs were synthesized and examined for their antiproliferative effects on a panel of carcinoma cells. Among the tested agents, only 34 exhibited a moderate activity with an IC50 value of 28.9 μM against PC-3 cells which indicates the selectivity of PC-3 cells in response to 2-styrylchromones. In addition, 38 demonstrated the most antiproliferative effect with an IC50 value of 4.9 μM against HeLa cells. Together, these results suggest a potential structural optimization and pharmacological study of 2-styrylchromones.

The second part : A series of Mannich-type reaction of 8-hydroxyquinoline derivatives are prepared which demonstrated apoptosis-inducing effect against HeLa cervical cancer cells. Among the tested compounds, 5-nitro-7-((4-tosylpiperazin-1-yl)methyl)quinolin-8-ol (115) exhibited the most anti-proliferative effect with an IC50 value of 0.7 μM. Further structure-activity relationship (SAR) study as well as pharmacological exploitation of this novel 8-hydroxyquinoline scaffold are underway.

目錄
目錄 I
圖表目錄 IV
第一章 緒論 1
1-1 癌症的簡介 1
1-2 藥物的設計動機 3
第二章 2-苯乙烯色素母酮衍生物當作抗癌試劑之研究 6
2-1 色素母酮簡介 6
2-2 結果與討論 9
2-3 結構與活性關係 16
2-3-1 2-苯乙烯色素母酮衍生物抑制PC-3前列腺癌細胞生長
之構效關係 17
2-3-2 2-苯乙烯色素母酮衍生物抑制A549肺腺癌細胞生長
之構效關係 18
2-3-3 2-苯乙烯色素母酮衍生物抑制BT483乳癌細胞生長
之構效關係 19
2-3-4 2-苯乙烯色素母酮衍生物抑制HeLa子宮頸癌細胞生長
之構效關係 20
2-3-5 2-苯乙烯色素母酮衍生物抑制SKHep肝癌細胞生長
之構效關係 20
2-4 結論 21
第三章 8-羥基喹啉衍生物當作抗癌試劑之研究 22
3-1 簡介 22
3-1-1 曼尼希反應介紹 22
3-1-2 8-羥基喹啉簡介 25
3-2 結果與討論 28
3-3 結構與活性關係 41
3-3-1 8-羥基喹啉衍生物抑制HeLa子宮頸癌細胞生長
之構效關係 44
3-3-2 8-羥基喹啉衍生物抑制BT483乳癌細胞生長
之構效關係 48
3-3-3 8-羥基喹啉衍生物抑制SKHep肝癌細胞生長
之構效關係 49
3-3-4 8-羥基喹啉衍生物抑制CE81T食道癌細胞生長
之構效關係 49
3-4 結論 50
第四章 實驗部分 51
4-1 實驗儀器及測試方法 51
4-2 溶劑的乾燥 53
4-3 2-苯乙烯色素母酮衍生物之實驗步驟及光譜資料 54
4-4 8-羥基喹啉衍生物之實驗步驟及光譜資料 78
第五章 參考文獻 117


圖表目錄
Figure 2-1 Flavopiridol的結構 6
Figure 2-2 Hormothamnione與6-Desmethoxyhormothamnione的結
構 7
Figure 2-3 2-styrylchromone的架構 9
Figure 3-1 Quinoline和8-hydroxyquinoline的化學結構 25
Figure 3-2 8-hydroxyquinolines衍生物52和90的化學結構 27
Figure 3-3 7-(morpholinomethyl)quinolin-8-ol的化學結構 29
Figure 3-4 胺類化合物的化學結構 29
Figure 3-5 Sulfonyl chloride和sulfonamide的化學結構 30
Figure 3-6 8-hydroxyquinolines衍生物52和90的化學結構及對
HeLa細胞之生物活性值 32
Figure 3-7 8-hydroxyquinolines衍生物90的化學結構
修飾部位A-D 33
Scheme 2-1 2-methyl-5,7-dimethoxychromone的逆合成分析 9
Scheme 2-2 2-styrylchromone 22-33的合成路徑 11
Scheme 2-3 2-styrylchromone 34-38的合成路徑 13
Scheme 3-1 Iminium ion形成的反應機制 23
Scheme 3-2 Mannich Reaction產物形成的反應機制 24
Scheme 3-3 Hydroxy aromatic的Mannich reaction之化學反應式 28
Scheme 3-4 以一鍋式四元素合成8-羥基喹啉衍生物的化學
反應式 30
Scheme 3-5 Sulfonamide二聚物63形成的化學反應式 31
Scheme 3-6 經由一鍋式三元素合成8-羥基喹啉衍生物90-106 的化
學反應式 32
Scheme 3-7 所合成出Sulfonamide中間產物73-89 (二級胺)的化學
反應式 34
Scheme 3-8 Benzamide二聚物形成的化學反應式 37
Scheme 3-9 二級胺類化合物66的合成反應式 38
Scheme 3-10 Sulfonamide中間產物107(一級胺)的化學反應式 39
Scheme 3-11 8-hydroxyquinolines衍生物108-110的化學反應式 39
Scheme 3-12 8-hydroxyquinolines衍生物111-117的化學反應式 40
Table 2-1 2-styrylchromone衍生物22-33的化學結構 12
Table 2-2 Acetophenone 8-16的化學結構 14
Table 2-3 化合物17-21和34-38的化學結構 15
Table 2-4 所測試的2-styrylchromone衍生物22–38之IC50值 16
Table 3-1 所合成出Sulfonamide中間產物73-89 (二級胺)的化學結構 35
Table 3-2 8-hydroxyquinoline衍生物91-106的化學結構 36
Table 3-3 Mannich-type reaction加合物111-117的化學結構 40
Table 3-4 所測試的8-hydroxyquinoline衍生物91-106之
IC50值 42
Table 3-5 所測試的8-hydroxyquinoline衍生物108-117之
IC50值 43

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