本論文主旨在設計並合成可抑制極光激酶(aurora kinases)之呋喃并嘧啶化合物，希望以此發展為抗癌標靶藥物。由知識基礎設計(knowledge-based design)所篩選出之潛力化合物1為改進對象，利用循理性設計及混成設計，分別發展出潛力化合物20及48，再從化合物與Aurora-A之共結晶結構中，發現這兩個潛力化合物之蛋白質結構屬於DFG-out及類DFG-out構型，並以共結晶結構分析來解釋蛋白質構型與生物活性之關係。同時以高通量平行合成(high-throughput parallel synthesis, HTPS)方法來加快合成衍生物之速度，挑選出適當化合物加以進行結構上之修飾，在加入脲基及末端苯環後，成功地發現先導化合物183，並從共結晶結構分析瞭解其結構與激酶之作用力，導致蛋白質結構改變為DFG-in構型，而展現極光激酶抑制劑之特性。接著利用各種合成方法進行先導化合物之最優化，確認最好之側鏈結構為乙基苯脲苯，並得到化合物252，成功降低化合物之分子量及親油性，並提昇其細胞活性。

This dissertation is concerned with the development of furano[2,3-d]pyrimidine compounds as Aurora kinases inhibitors. Start from compound 1, we utilize rational drug design to synthesize two particular hits, compound 20 and 48. We analyze the co-crystal structures of two hits with Aurora-A, and observe the protein structures belong to DFG-out and DFG-out-like conformation. At the same time, we apply high-throughput parallel synthesis (HTPS) to accelerate the synthesis of analogues. Fortunately, we discover the lead compound 183 which was modified from compound 145 by forming the urea functionality and terminal phenyl group. We analyze the co-crystal structure of compound 183, and find the protein structure is DFG-in conformation. The variety does not only display in protein conformation but also improve the bioactivity. After lead optimization, we confirm the ethyl-phenyl-urea was the best side chain structure, and find compound 252 which successfully improve the cell bioactivity and reduce the molecular weight and lipophilicity.

目 錄

中文摘要 i
英文摘要 ii
謝誌 iii
目錄 iv


一、緒論 1
1.1 癌症簡介 1
1.2 癌症起因 3
1.3 癌症治療 6
1.3.1 癌症化療藥物之分類 10
1.3.1.1 烷化劑藥物 11
1.3.1.2 抗代謝藥物 11
1.3.1.3 天然物 13
1.3.1.4 抗血管增生藥物 19
1.3.1.5 激酶抑制劑 20
1.3.2 標靶治療 24
1.3.3 抗癌藥物的市場概況 26
1.4 極光激酶 27
1.4.1 極光激酶之作用機制 28
1.4.1.1 Aurora-A之作用機制 29
1.4.1.2 Aurora-B之作用機制 30
1.4.2 以極光激酶為抗癌標的 31
1.4.3 極光激酶抑制劑之發展 33
1.4.3.1 Hesperadin 33
1.4.3.2 MK0457 (VX-680) 34
1.4.3.3 AZD1152 35
1.4.3.4 PHA-680632及PHA-739358 36
1.4.3.5 MLN8054 37
1.4.3.6 CCT129202 38
1.4.3.7 MP529 38
1.4.3.8 SNS-314 39
1.4.3.9 AT9283 40

二、研究構思 41
2.1 研究動機 41
2.2 文獻回顧 44
2.2.1 呋喃并嘧啶之合成文獻回顧 44
2.2.2 呋喃并嘧啶之生物活性文獻回顧 46
2.3 研究構想 52
2.4 生物活性測試分析 57
2.4.1 酵素活性測試分析法 57
2.4.2 細胞活性測試分析法 58

三、結果與討論 61
3.1 合成策略 61
3.2 循理性藥物設計 63
3.2.1 芳香胺化合物之設計 64
3.2.2 芳香胺化合物之合成 65
3.2.3 芳香胺化合物之生物活性分析 70
3.2.4 芳香胺化合物之共結晶結構分析 73
3.2.5 混成設計 78
3.2.6 混成設計之合成 79
3.2.7 混成設計之生物活性分析 82
3.2.8 混成設計之共結晶結構分析 85
3.2.9 循理性藥物設計之結論 92
3.3 高通量平行合成設計 93
3.3.1 高通量平行合成之方法 93
3.3.2 高通量平行合成之生物活性分析 95
3.3.3高通量平行合成之結論 108
3.4 高通量平行合成化合物之結構修飾 110
3.4.1 高通量平行合成化合物結構修飾之合成 112
3.4.1.1 哌嗪化合物之合成 112
3.4.1.2 乙基苯化合物之合成 116
3.4.2 高通量平行合成化合物結構修飾之生物活性分析 118
3.4.2.1 哌嗪化合物之生物活性分析 118
3.4.2.2 乙基苯化合物之生物活性分析 123
3.4.3 先導化合物之功能性生物活性分析 124
3.4.4 先導化合物之共結晶結構分析 129
3.4.5 高通量平行合成化合物結構修飾之結論 138
3.5 先導化合物最優化. 139
3.5.1 先導化合物最優化之設計 140
3.5.2 先導化合物最優化之合成 140
3.5.2.1 改變脲基官能基化合物之合成 140
3.5.2.2 移動脲基位置化合物之合成 142
3.5.2.3 改變末端苯環化合物之合成 144
3.5.2.4 增加末端苯環取代基化合物之合成 147
3.5.2.5 移動中間苯環化合物之合成 148
3.5.2.6 延伸乙基鏈結化合物之合成 149
3.5.2.7 改變四號位置氮取代化合物之合成 151
3.5.2.8 改變五、六號位置苯環化合物之合成 152
3.5.2.9 改變中間苯環化合物之合成 155
3.5.3 先導化合物最優化之生物活性分析 157
3.5.4 先導化合物與SNS-314之比較 169
3.5.4.1 先導化合物與SNS-314於生物活性之比較 169
3.5.4.2 先導化合物與SNS-314於共結晶結構之比較 175
3.5.5 先導化合物最優化之結論 177

四、總結 179

五、實驗部份 186
5.1 一般實驗方法 186
5.2 化合物之實驗步驟及光譜資料 188

參考資料 275

附錄一 天然物Pelseneeriol之合成研究 284
附錄二 化合物之ligplot圖 311
附錄三 化合物之核磁共振光譜圖 320
附錄四 生物活性測試分析方法 433
附錄五 化合物編號對照表 436

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