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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