臺灣博碩士論文加值系統

近年來，三陰性乳癌具有高死亡、高復發及高腦部轉移等特性，成為女性乳癌中最棘手的疾病之一。目前對於三陰性乳癌的化學治療方式選擇很少，主要以手術治療及放射性治療，而化學治療時常出現抗藥性，因此本實驗室致力於開發治療三陰性乳癌的藥物，希望可以幫助病人降低三陰性乳癌對她們的威脅。
為了開發新的抗癌藥物，我們透過高速藥物篩選系統篩選出N-(2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl)-4-isobutyl- N-methyl benzenesulfonamide (YL-18) 做為先導藥物，但嘗試幾種合成路徑無法得到預期產物，因此將結構改為N-(2-(1-ethyl-3,5-dimethyl-1H- pyrazol-4-yl)ethyl)-4-isobutylbenzamide (YL-66)，接著，以吡唑做為骨架，進行化學結構的優化，藉此提高細胞毒性。
首先進行官能基的轉換，結果發現以胺類化合物的細胞毒性較醯胺類化合物強，且較不具有介質的選擇性；接著進行一系列取代基的更換，分別有親水性、疏水性、拉電子基和推電子基這幾類取代基做比較，經過生物測試得知結構以疏水性的取代基細胞毒性最強，即為化合物YL-81，對三陰性乳癌MDA-MB-231細胞株於DMEM及L15兩種介質中，IC50 分別為 9.76 µM及0.5 µM。接著比較二級及三級胺類化合物，經由實驗結果顯示，仍然以二級胺類化合物YL-81的細胞毒性最強。

Triple negative breast cancer (TNBC) has high mortality rate, high recurrence and high brain metastasis. Chemotherapy is the only treatment, and the worst of all it develops drug resistance. Therefore, we devote to drug discovery and synthesis for alleviating the suffering of patients.
According to the previous research, the derivatives of pyrazole scaffold have activity against cancer. Hence, we study pyrazole compound N-(2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl)-4-isobutyl- N-methylbenzenesulfonamide (YL-18), which is chosen as the hit compound through high throughput screening approach in order to discover anti-cancer agent for treatment of TNBC. However, I don’t get desire compound (YL-18) through several synthetic routes, we change YL-18 to N-(2-(1-ethyl-3,5-dimethyl-1H- pyrazol-4-yl)ethyl)-4-isobutyl benzamide (YL-66).
The first generation compounds containing amine and amide bond of pyrazole derivatives was synthesized. We observed that pyrazole derivatives with amine group had better anti-cancer activity than amide group. In addition, the amine compounds don’t have the medium-dependent effect in the cytotoxic assay. The second generation compounds focused on several substituents at 4- position of benzene group. We found that there is no difference between electron withdrawing groups and electronic donating groups at benzene ring. Then, we compared hydrophobic substituents with hydrophilic substituents at C4 position of benzene ring; the results showed that compound YL-81 with hydrophobic substituents has better anti-cancer activity than others. In desire of the third generation compounds, we converted the secondary amine into tertiary amines, but they didn’t have enhancement of anti-cancer activity. In summary, compound YL-81 possesses potent anti proliferative activity against triple negative breast cancer MDA-MB-231 cells in DMEM and L15 medium with IC50 values of 9.76 and 0.5 µM, respectively.

摘要 I
Abstract II
誌謝 IV
目錄 V
流程目錄 VIII
圖目錄 X
表目錄 XI
一、 緒論 1
1.1 前言 1
1.2 三陰性乳癌的介紹 2
1.3 目前使用於三陰性乳癌的治療方式 2
1.3.1 外科治療 3
1.3.2 小紅莓類藥物 3
1.3.3 紫杉醇類藥物 5
1.3.4 鉑化合物 6
1.3.5 針對非HER-2/neu的標靶藥物治療 7
1.4 吡唑(Pyrazole)的衍生藥物 8
1.5 研究動機 8
二、 實驗結果與討論 10
2.1 目標分子的逆合成分析 10
2.2 合成化合物YL-61 12
2.3 合成Pyrazole的衍生物 14
2.4 生物活性結果與討論 22
三、 結論 27
四、 實驗部分 29
4.1 實驗藥品 29
4.2 分析技術 32
4.2.1 核磁共振光譜儀 32
4.2.2 高解析度質譜 32
4.2.3 高效液相層析儀 33
4.2.4 冷凍乾燥 33
4.2.5 薄片層析 33
4.2.6 減壓濃縮機 33
4.2.7 沖提液、展開液、萃取使用溶液 34
4.2.8 實驗使用之反應試劑及溶劑 34
4.2.9 使用無水溶劑之反應條件 34
4.2.10 Ninhydrin顯色劑配置 34
4.2.11 高錳酸鉀顯色劑配置 34
4.3 實驗方法 35
4.3.1 化合物YL-66的合成方法 35
4.3.2 化合物YL-67的合成方法 38
4.3.3 化合物YL-73的合成方法 39
4.3.4 化合物YL-76的合成方法 41
4.3.5 化合物YL-77的合成方法 43
4.3.6 化合物YL-78的合成方法 44
4.3.7 化合物YL-80的合成方法 46
4.3.8 化合物YL-81的合成方法 47
4.3.9 化合物YL-84的合成方法 49
4.3.10 化合物YL-87的合成方法 50
4.3.11 化合物YL-88的合成方法 52
4.3.12 化合物YL-89的合成方法 53
4.3.13 化合物YL-90的合成方法 55
4.3.14 化合物YL-91的合成方法 57
4.3.15 化合物YL-92的合成方法 58
4.3.16 化合物YL-93的合成方法 60
4.3.17 化合物YL-94的合成方法 61
4.3.18 化合物YL-95的合成方法 63
4.3.19 化合物YL-96的合成方法 64
4.3.20 化合物YL-97的合成方法 66
五、 參考文獻 68
六、 圖譜附錄 72

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