系統識別號 | U0002-2008200905514100 |
---|---|
DOI | 10.6846/TKU.2009.00741 |
論文名稱(中文) | 3,5-1H-雙芳基吡唑衍生物之合成暨抑制SK-OV-3卵巢癌細胞生長之構效關係研究 |
論文名稱(英文) | Synthesis of 3,5-1H-Diarylpyrazole Derivatives and Structure-Activity Relationship Study of Growth Inhibition Against SK-OV-3 Ovarian Cancer Cells |
第三語言論文名稱 | |
校院名稱 | 淡江大學 |
系所名稱(中文) | 化學學系碩士班 |
系所名稱(英文) | Department of Chemistry |
外國學位學校名稱 | |
外國學位學院名稱 | |
外國學位研究所名稱 | |
學年度 | 97 |
學期 | 2 |
出版年 | 98 |
研究生(中文) | 廖浩涵 |
研究生(英文) | Hao-Han Liau |
學號 | 696160299 |
學位類別 | 碩士 |
語言別 | 繁體中文 |
第二語言別 | |
口試日期 | 2009-06-23 |
論文頁數 | 176頁 |
口試委員 |
指導教授
-
蕭永政(shaw299@mail.tku.edu.tw)
委員 - 蕭崇瑋 委員 - 鄧金培 |
關鍵字(中) |
吡唑 構效關係 SK-OV-3卵巢癌細胞 |
關鍵字(英) |
pyrazole Structure-Activity Relationship SK-OV-3 |
第三語言關鍵字 | |
學科別分類 | |
中文摘要 |
本論文中我們設計了3,5-雙芳基-1H-吡唑化合物,一個簡單的分子骨架來做為抗癌的試劑。以簡單的合成方法,將苯乙酮化合物和醯氯化合物在甲苯中以六甲基二矽基胺基鋰合成1,3-雙酮化合物。之後把反應得到的混合物經過萃取和濃縮的處理,不再進一步的純化,直接在乙醇中和聯胺反應得到3,5-雙芳基-1H-吡唑化合物。再以相同的合成方法,將反應中的聯胺改為羥胺,合成了3,5-雙苯基異噁唑化合物的結構異構物混合物,且發現這個反應的化學選擇性會受到其苯環上的取代基影響。 在抑制SK-OV-3卵巢癌細胞生長的實驗中,藉由改變3,5-雙苯基-1H-吡唑化合物的官能基來觀察其結構與抑制SK-OV-3卵巢癌細胞生長的關係。由實驗結果發現3,5-雙苯基-1H-吡唑化合物做為SK-OV-3卵巢癌細胞生長抑制劑的最佳化結構:其一邊苯環上須有拉電子基,另一邊的苯環上則須為推電子基。推電子基如甲氧基在3號位置最佳,若4號位置上有氫鍵供給者像是羥基或胺基時,其抑制SK-OV-3卵巢癌細胞生長的能力可得到不錯的效果。 當我們將3,5-雙苯基-1H-吡唑化合物一邊的苯基改為1,1’-聯苯基時,其抑制SK-OV-3卵巢癌細胞的效果更好。由實驗結果發現固定3,5-雙芳基-1H-吡唑化合物一邊為1,1’-聯苯基時的最佳化結構:當苯環上有取代基使得吡唑結構中氮上的氫可以固定在靠近1,1’-聯苯基的氮上,可提升抑制SK-OV-3卵巢癌細胞生長的效果。此外,苯環上的4號位置上為氫鍵供給者時,其抑制SK-OV-3卵巢癌細胞生長的效果會下降。綜合實驗結果,發現化合物64(第53頁)和68(第55頁)為抑制SK-OV-3卵巢癌細胞生長的效果最好的3,5-雙芳基-1H-吡唑化合物,其IC50分別為0.6 ± 0.14 μM和0.5 ± 0.14 μM。 |
英文摘要 |
In this dissertation, we synthesized a series of 3, 5-diaryl-1H-pyrazole derivatives containing a simple molecular scaffold for the study of growth inhibitory effect in cancer cells. We took advantage of a practical synthetic route to synthesize these derivatives as shown in the followings: The 1,3-diketone intermediate was prepared by the treatment of acetophenone and benzoyl chloride in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) in toluene solution. Without further purification, 1,3-diketone intermediate was treated with hydrazine and heated at reflux in ethanol solution to afford the desired products. In a similar manner, two isomers of isoxazoles were obtained by treatment of 1,3-diketone with hydroxylamine in ethanol solution. In addition, the selectivity of two isomers was dependent of substituted groups on the aromatic ring. The growth inhibitory effect of all tested compounds was examined in the SK-OV-3 ovarian cancer cells. The results indicated that the most potent growth inhibition could be observed as one aromatic ring bearing an electron-withdrawing group while the another containing an electron-donating group in the 3,5-diaryl-1H-pyrazole scaffold. Moreover, as an electron-donating group such as methoxy group (48, IC50 = 15 ± 2 μM, page 48) located at 3-position as well as a hydrogen bond donor such as hydroxyl (77, IC50 = 10 ± 2 μM, page 52) and amino groups (78, IC50 = 18 ± 2 μM, page 52) at 4-position exhibited better growth inhibitory effects. Surprisingly, as one aromatic group attached to the pyrazole core was replaced with a 1,1’-biphenyl group, an improved growth inhibitory effect on SK-OV-3 cells was observed. We found that 79 (2-OH on the benzene ring, IC50 = 10 ± 1 μM, page 55) maintaining the tautomerism of pyrazole in which NH closed to the 1,1’-biphenyl group revealed a better growth inhibitory as compared to its counterpart 66 (2-OMe, IC50 = 34 ± 3 μM, page 55). Meanwhile, as a hydrogen bond donor such as hydroxyl group at 4-position (80, 4-OH, IC50 = 27 ± 4 μM, page 55) exhibited a poor growth inhibitory effect in comparison with its counterpart (64, 4-OMe, IC50 = 0.6 ± 0.14 μM, page 53). Taken together, we have synthe-sized a series of 3, 5-diaryl-1H-pyrazole derivatives that exhibited some interesting structure activity relationships in the study of growth inhibi-tion of SK-OV-3 ovarian cancer cells. To further improve their physical properties such as water solubility as drug-like compounds, structural modifications of 3,5-diaryl-1H-pyrazole-based anticancer agents could be further explored in the near future. |
第三語言摘要 | |
論文目次 |
目錄 目錄............................................................................................................I 圖表目錄..................................................................................................III 光譜目錄.................................................................................................VII 第一章 緒論 1 1-1 吡唑化合物簡介 4 1-2 已知藥理活性吡唑化合物概述 5 1-3 3,5-雙苯基-1H-吡唑(3,5-Diphenyl-1H-pyrazoles)的合成方法探討 20 1-3-1 利用分子內合環合成3,5-雙苯基-1H-吡唑 21 1-3-2 利用分子間合環合成3,5-雙苯基-1H-吡唑 22 1-3-3 其他合成3,5-雙苯基-1H-吡唑的方法 33 1-4 SK-OV-3卵巢癌細胞簡介 35 1-4-1 卵巢癌簡介 36 1-4-2 SK-OV-3卵巢癌細胞簡介 38 1-5 研究動機與目的 39 第二章 結果與討論 40 2-1 3,5-雙芳基-1H-吡唑化合物(3,5-Diaryl-1H-pyrazoles)之 合成 40 2-2 3,5-雙芳基-1H-吡唑化合物(3,5-Diaryl-1H-pyrazoles) 抑制SK-OV-3卵巢癌細胞生長之構效關係 46 2-3 結論 56 第三章 實驗與儀器 61 3-1 實驗儀器與測試方法 61 3-2 溶劑的乾燥 63 3-3 反應條件及實驗步驟 64 附錄一 光譜資料....................................................................................90 附錄二 參考資料..................................................................................163 圖表目錄 Figure 1-1 雙異原子不飽和五圓雜環 3 Figure 1-2 Pirazolac和Difenamizole的化學結構 5 Figure 1-3 環氧化酶和5-脂氧合酶的抑制劑 6 Figure 1-4 環氧化酶-2的選擇性抑制劑 7 Figure 1-5 BIRB 796和RO3201195的化學結構 8 Figure 1-6 p38 MAPK的訊號傳遞路徑與發炎反應的關係構............9 Figure 1-7 CB抑制劑............................................................................10 Figure 1-8 CB1的訊號傳遞抑制腺苷酸環化酶並活化絲裂原活化蛋白激酶..................................................................................11 Figure 1-9 組織胺和其相物.................................................................12 Figure 1-10 Mepiprazole的化學結構...................................................12 Figure 1-11 雌激素受器-α選擇性拮抗劑............................................13 Figure 1-12 Sulfaphenazole和Sulfazamet的化學結構 14 Figure 1-13 DNA促旋酶抑制劑 15 Figure 1-14 凝血因子Xa抑制劑 16 Figure 1-15 XRP44X的化學結構 16 Figure 1-16 Net的蛋白質結構 17 Figure 1-17 熱休克蛋白90抑制劑 18 Figure 1-18 奧羅拉激酶抑制劑 19 Figure 1-19 1,3-雙苯基-1,3-丙雙酮化合物、1,3-雙苯基-2-丙烯-1-酮化合物和1,3-雙苯基-2-丙炔-1-酮化合物化合物 24 Figure 2-1 經由分子內氫鍵固定吡唑結構中氮上的氫原子 54 Figure 2-2 3,5-雙苯基-1H-吡唑化合物的最佳化結構 58 Figure 2-3 固定3,5-雙芳基-1H-吡唑化合物一邊為1,1’-聯苯基時的最佳化結構 59 Scheme 1-1 吡唑化合物的環內互變異構.............................................4 Scheme 1-2 最早的3,5-雙苯基-1H-吡唑的合成方法.........................20 Scheme 1-3 利用β-腙基酮類化合物合成3,5-雙苯基-1H-吡唑.........21 Scheme 1-4 利用醯肼類化合物合成3,5-雙苯基-1H-吡唑.................22 Scheme 1-5 利用[3+2]環加成反應合成3,5-雙苯基-1H-吡唑............23 Scheme 1-6 以1,3-雙苯基-1,3-丙雙酮化合物合成3,5-雙苯基-1H-吡 唑.........................................................................................25 Scheme 1-7 經由三酮中間產物造成化學位相選擇的不規則 26 Scheme 1-8 利用1,3-雙苯基-2-丙烯-1-酮化合物無法直接合成3,5-雙苯基-1H-吡唑 27 Scheme 1-9 在吡唑啉的4號位置插入離去基X,以利於吡唑啉化合物脫去HX而形成吡唑化合物 28 Scheme 1-10 4號位置插入離去基X的吡唑啉化合物的逆合成分析 28 Scheme 1-11 利用乙酸環丙酯合成3,5-雙苯基-1H-吡唑 29 Scheme 1-12 利用碘或碘化鈉合成3,5-雙苯基-1H-吡唑 30 Scheme 1-13 利用環氧化合物合成3,5-雙苯基-1H-吡唑 30 Scheme 1-14 利用吖丙啶合成3,5-雙苯基-1H-吡唑 31 Scheme 1-15 利用硫合成3,5-雙苯基-1H-吡唑 31 Scheme 1-16 利用聯胺自由基合成3,5-雙苯基-1H-吡唑...................32 Scheme 1-17 1,3-雙苯基-2-丙烯-1-酮化合物的製備..........................32 Scheme 1-18 利用1,3-雙芳基丙-2-炔-1-酮化合物合成3,5-雙苯基 -1H-吡唑...............................................................................33 Scheme 1-19 利用鈀催化四元素偶合反應合成3,5-雙苯基-1H-吡唑 ............................................................................................34 Scheme 2-1 3,5-雙芳基-1H-吡唑化合物的製備方法 40 Scheme 2-2 Heller和Natarajan的製備方法 42 Scheme 2-3 修改後的製備方法 43 Scheme 2-4 3,5-雙苯基異噁唑化合物的製備 44 Scheme 3-1 3,5-雙芳基-1H-吡唑化合物的製備 65 Scheme 3-2 3-芳基-5-硝基-1H-吡唑化合物的製備 81 Scheme 3-3 3-芳基-5-甲氧基-1H-吡唑化合物的製備 85 Scheme 3-4 羥基苯乙酮化合物的製備 88 Scheme 3-5 苯甲醯氯化合物的製備 89 Table 1-1 SK-OV-3細胞株基本資料 38 Table 2-1 化合物69a,b - 71a,b其異噁唑結構上的氫在NMR光譜中的化學位移以及其異構物間的比例 45 Table 2-2 化合物45 - 55的結構與IC50 48 Table 2-3 化合物56 - 60以及72 - 78的結構與IC50...........................52 Table 2-4 化合物64 - 68以及79 - 81的結構與IC50...........................55 Table 3-1 製備3,5-雙芳基-1H-吡唑化合物所使用的苯乙酮化合物及 醯氯化合物............................................................................65 光譜目錄 化合物45之1H NMR (300 MHz, DMSO-d6) 90 化合物45之13C NMR (75 MHz, DMSO-d6) 91 化合物46之1H NMR (300 MHz, DMSO-d6) 92 化合物46之13C NMR (75 MHz, DMSO-d6) 93 化合物47之1H NMR (300 MHz, DMSO-d6) 94 化合物47之13C NMR (75 MHz, DMSO-d6) 95 化合物48之1H NMR (300 MHz, DMSO-d6) ..............................................96 化合物48之13C NMR (75 MHz, DMSO-d6) ...............................................97 化合物49之1H NMR (300 MHz, DMSO-d6) ........................................98 化合物49之13C NMR (75 MHz, DMSO-d6) .........................................99 化合物50之1H NMR (300 MHz, DMSO-d6) ......................................100 化合物50之13C NMR (75 MHz, DMSO-d6) .......................................101 化合物51之1H NMR (300 MHz, DMSO-d6).......................................102 化合物51之13C NMR (75 MHz, DMSO-d6). 103 化合物52之1H NMR (300 MHz, DMSO-d6) 104 化合物52之13C NMR (75 MHz, DMSO-d6) 105 化合物53之1H NMR (300 MHz, DMSO-d6) 106 化合物53之13C NMR (75 MHz, DMSO-d6) 107 化合物54之1H NMR (300 MHz, DMSO-d6) 108 化合物54之13C NMR (75 MHz, DMSO-d6) 109 化合物55之1H NMR (300 MHz, DMSO-d6) 110 化合物55之13C NMR (75 MHz, DMSO-d6) 111 化合物56之1H NMR (300 MHz, DMSO-d6) 112 化合物56之13C NMR (75 MHz, DMSO-d6) 113 化合物57之1H NMR (300 MHz, DMSO-d6) 114 化合物57之13C NMR (75 MHz, DMSO-d6) .......................................115 化合物58之1H NMR (300 MHz, DMSO-d6) ......................................116 化合物58之13C NMR (75 MHz, DMSO-d6) .......................................117 化合物59之1H NMR (300 MHz, DMSO-d6) ......................................118 化合物59之13C NMR (75 MHz, DMSO-d6) .......................................119 化合物60之1H NMR (300 MHz, DMSO-d6) ......................................120 化合物60之13C NMR (75 MHz, DMSO-d6) 121 化合物61之1H NMR (300 MHz, DMSO-d6) 122 化合物61之13C NMR (75 MHz, DMSO-d6) 123 化合物62之1H NMR (300 MHz, DMSO-d6) 124 化合物62之13C NMR (75 MHz, DMSO-d6) 125 化合物63之1H NMR (300 MHz, DMSO-d6) 126 化合物63之13C NMR (75 MHz, DMSO-d6) 127 化合物64之1H NMR (300 MHz, DMSO-d6) 128 化合物64之13C NMR (75 MHz, DMSO-d6) 129 化合物65之1H NMR (300 MHz, DMSO-d6) 130 化合物65之13C NMR (75 MHz, DMSO-d6) 131 化合物66之1H NMR (300 MHz, DMSO-d6) 132 化合物66之13C NMR (75 MHz, DMSO-d6) 133 化合物67之1H NMR (300 MHz, DMSO-d6) ......................................134 化合物67之13C NMR (75 MHz, DMSO-d6) .......................................135 化合物68之1H NMR (300 MHz, DMSO-d6) ......................................136 化合物68之13C NMR (75 MHz, DMSO-d6) .......................................137 化合物69a和69b之1H NMR (300 MHz, CDCl3-d1) ..........................138 化合物70a和70b之1H NMR (300 MHz, CDCl3-d1) ..........................139 化合物71a和71b之1H NMR (300 MHz, CDCl3-d1) 140 化合物72之1H NMR (300 MHz, DMSO-d6) 141 化合物72之13C NMR (75 MHz, DMSO-d6) 142 化合物73之1H NMR (300 MHz, DMSO-d6) 143 化合物73之13C NMR (75 MHz, DMSO-d6) 144 化合物74之1H NMR (300 MHz, CDCl3-d1) 145 化合物74之13C NMR (75 MHz, CDCl3-d1) 146 化合物75之1H NMR (300 MHz, DMSO-d6) 147 化合物75之13C NMR (75 MHz, DMSO-d6) 148 化合物76之1H NMR (300 MHz, DMSO-d6) 149 化合物76之13C NMR (75 MHz, DMSO-d6) 150 化合物77之1H NMR (300 MHz, DMSO-d6) 151 化合物77之13C NMR (75 MHz, DMSO-d6) 152 化合物78之1H NMR (300 MHz, DMSO-d6) ......................................153 化合物78之13C NMR (75 MHz, DMSO-d6) .......................................154 化合物79之1H NMR (300 MHz, DMSO-d6) ......................................155 化合物79之13C NMR (75 MHz, DMSO-d6) .......................................156 化合物80之1H NMR (300 MHz, DMSO-d6) ......................................157 化合物80之13C NMR (75 MHz, DMSO-d6) .......................................158 化合物81之1H NMR (300 MHz, DMSO-d6) 159 化合物81之13C NMR (75 MHz, DMSO-d6) 160 化合物83之1H NMR (300 MHz, CDCl3-d1) 161 化合物83之13C NMR (75 MHz, CDCl3-d1) 162 |
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