臺灣博碩士論文加值系統

一系列產率高之含肟及甲基肟之黃酮和異黃酮衍生物已被合成，它們是由3-, 6-, 7-位取代之黃酮和7-位取代之異黃酮分別先進行烷化反應後再與NH2OH或NH2OCH3進行親核性加成反應而得。其中一些含肟取代之衍生物對於花生四烯酸(arachidonic acid)及膠原(collagen)所誘發的血小板凝集有良好的抑制活性。比較其對血小板的抑制活性，依側鏈所接的位置不同而遞減順序為：7-位取代異黃酮＞7-位取代黃酮＞3-位取代黃酮＞6-位取代黃酮。其中以(E)-7-(2-hydroxyiminopropoxy)-3-phenyl-4H-1-benzopyran-4- one (15a) 對AA所誘導的抗血小板凝集有最好的活性，所得的IC50值為2.97 ± 0.4 µM。含肟及甲基肟之黃酮及異黃酮類衍生物也進行其對抗細胞增生活性評估，先針對乳癌(MCF7)，肺癌(NCI-H460)和中樞神經癌(SF-268)這三株癌細胞進行初步篩選，而有活性之化合物再更進一步對六十株人類癌細胞進行活性評估。結果顯示衍生物(Z)-6-(2-hydroxyimino-2-phenylethoxy)-2-phenyl-4H-1-benzo pyran-4-one (7b)、(Z)-6-[2-hydroxyimino-2-(4-methoxyphenyl) ethoxy]-2-phenyl-4H-1-benzopyran-4-one (7d)和(E)-6-(2- methoxyiminopropoxy)-2-phenyl-4H-1-Benzopyran-4-one (8a) 三個具有最佳的抗細胞增生活性，對於抑制肝癌細胞(SKHep1)成長，其GI50值分別為0.7 ± 0.2, 0.8 ± 0.3和0.8 ± 0.8 �嵱; 而對於抑制子宮頸癌細胞(HeLa)成長，其GI50值分別為0.8 ± 0.2, 1.0 ± 1.1和0.9 ± 0.2�n�嵱。其中，衍生物7d不但對60株人類腫瘤細胞有最好的細胞毒性，其平均GI50為0.08 μΜ，而且是此系列flavone衍生物中，唯一對口腔麟狀癌細胞(SAS)抑制活性GI50值小於1 μM之衍生物。從流式細胞儀分析(flow cytometric analyses)實驗機轉指出，化合物7d其能抑制子宮頸癌(HeLa)細胞生長週期的G2/M時期而造成癌細胞凋亡。

A number of flavone and isoflavone derivatives with oxime and methyloxime substituted were synthesized by 3-, 6-, 7-hydroxyflavone, or 7-hydroxyisoflavone via alkylation and nucleophilic addition with NH2OH or NH2OMe in a good yield. Certain oxime-substituted derivatives showed moderate inhibitory activities against platelet aggregation induced by arachidonic acid (AA), and collagen (Col). Comparing the different chromophores established the following order of decreasing potency: 7-substituted-isoflavones > 7-substituted-flavones > 3-substituted-flavones > 6-substituted-flavones. Among them, (E)-7-(2-hydroxyimino propoxy)-3-phenyl-4H-1-benzopyran-4-one (15a) was the most active against AA induced platelet with an IC50 of 2.97 ± 0.4 μΜ. The synthetic flavone and isoflavone derivatives were also evaluated for antiproliferative activity against three cancer cells consisting of MCF7 (breast), NCI-H460 (lung), and SF-268 (CNS), and the active compounds passed on for evaluation in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results indicated (Z)-6-(2-hydroxyimino-2-phenylethoxy)-2-phenyl-4H-1-benzo pyran-4-one (7b), (Z)-6-[2-hydroxyimino-2-(4-methoxy phenyl)ethoxy]-2-phenyl-4H-1-benzopyran-4-one (7d)和(E)-6- (2-methoxyiminopropoxy)-2-phenyl-4H-1-Benzopyran-4-one (8a) are three of the best antiproliferative agents with GI50 values of 0.7 ± 0.2, 0.8 ± 0.3, and 0.8 ± 0.8 μM, respectively, against the growth of SKHep1 (hepatocelluar carcinoma); 0.8 ± 0.2, 1.0 ± 1.1, and 0.9 ± 0.2 μM, respectively, against the growth of HeLa (human cervical epithelioid carcinoma) cells. Compound 7d is not only the most cytotoxic with a mean GI50 value of 0.08 μM against the full panel of 60 human tumor cell lines but also the only flavone derivatives that exhibited GI50 value of less than 1 μM against the growth of SAS (oral sqamous cell carcinoma). Flow cytometric analyses revealed that growth inhibition by 7d was due to accumulation in G2/M phase arrest and followed by apoptosis.

中文摘要 ………………………………………………………………………… Ⅰ
英文摘要 ………………………………………………………………………… Ⅲ
誌謝 ………………………………………………………………………… Ⅴ
目錄 ………………………………………………………………………… Ⅵ
圖目錄 …………………………………………………………………………… Ⅸ
表目錄 …………………………………………………………………………… Ⅹ

第壹章 緒論 ………………………………………………………………… 1
第一節 前言 ………………………………………………………………… 1
第二節 研究動機與目的 ………………………………………………… 7
第貳章 合成方法與步驟 ………………………………………………… 11
第一節 合成大綱…………………………………………………………… 11
第二節 合成步驟與方法 ………………………………………………… 12
一、3-位含肟與甲基肟之黃酮衍生物3與4的合成 ………………… 12
二、6-位含肟及甲基肟之黃酮衍生物7 與8的合成 ………………… 14
三、7-位含肟及甲基肟之黃酮衍生物11與12的合成 ……………… 16
四、7-位含肟及甲基肟之異黃酮衍生物15與16的合成 …………… 18
第參章 生物活性評估 ………………………………………………… 20
第一節 抗血小板凝集活性試驗 ……………………………… 20
一、實驗方法………………………………………………………………… 20
二、初步結果………………………………………………………………… 22
三、結果與討論………………………………………………… 22
1. 3-位含肟及甲基肟黃酮衍生物3與4之抗血小板活性評估……… 22
2. 6-位含肟及甲基肟黃酮衍生物7與8之抗血小板活性評估……… 24
3. 7-位含肟及甲基肟黃酮衍生物11與12之抗血小板活性評估…… 26
4. 7-位含肟及甲基肟異黃酮衍生物15與16之抗血小板活性評估… 28
第二節 細胞毒活性試驗………………………………………………… 30
一、結果與討論……………………………………………………………… 31
第三節 檢測化合物7d對子宮頸癌(HeLa)細胞週期的影響……… 35
第肆章 實驗部份 …………………………………………………………… 37
第一節 儀器與試藥………………………………………………………… 37
一、儀器 ………………………………………………………………………… 37
二、試藥 ………………………………………………………………………… 38
第二節 各化合物的製備…………………………………………………… 39
一、3-位含肟之黃酮衍生物之製備(3a-e)………………………………… 39
二、3-位含甲基肟之黃酮衍生物之製備(4a-e) ………………………… 44
三、6-位含肟之黃酮衍生物之製備(7a-e)………………………………… 49
四、6-位含甲基肟之黃酮衍生物之製備(8a-e) ………………………… 54
五、7-位含肟之黃酮衍生物之製備(11a-e) ……………………………… 59
六、7-位含甲基肟之黃酮衍生物之製備(12a-e) ……………………… 64
七、7-位肟之異黃酮衍生物之製備(15a-e) ……………………………… 69
八、7-位含甲基肟之異黃酮衍生物之製備(16 a-e)……………………… 74
第伍章 總結………………………………………………………………… 79
參考文獻………………………………………………………………………… 81
研究成果目錄 …………………………………………………………………… 83
A、投稿論文 …………………………………………………………………… 83
B、學會發表論文………………………………………………………………… 83

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