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研究生:陳俐君
研究生(外文):Chen, Li-Chun
論文名稱:噁唑并嘧啶類北極光激酶抑制劑之研究
論文名稱(外文):Design and Synthesis of Oxazolo[4,5- d]pyrimidine Compounds as Aurora Kinase Inhibitors
指導教授:張大慈謝興邦謝興邦引用關係徐祖安
指導教授(外文):Chang, Margaret Dah-TsyrHsieh, Hsing-PangHsu, John Tsu-An
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:85
中文關鍵詞:北極光激&北極光激&北極光激&北極光激&
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  北極光激酶(Aurora Kinases)是一種調控有絲分裂的絲胺酸/蘇胺酸激酶(Serine/threonine),哺乳動物中可分為三種─北極光激酶A、B和C。許多文獻已指出北極光激酶與細胞癌化(tumorigenesis)間密切的關係,甚至認為極光激酶A為一種致癌蛋白。本論文以北極光激酶為標靶,探討噁唑并嘧啶(oxazolopyrimidine)系列化學結構與北極光激酶抑制活性之相關性(structure-activity relationship,簡稱SAR)。研究方向分為三個部分:化學合成研究、類藥性質分析,以及生物活性測試。合成方面係利用威廉森反應(Williamson type O-alkylation)在主結構上引入各種親水性含氮鹼基,此系列類似物對北極光激酶A的抑制性均維持在1 μM (IC50)以下。溶解度測定則依熱力學法進行定量分析,結果顯示結構上具有親水性含氮鹼基的化合物確實可提升溶解度,尤其以N-methylpiperazine修飾之化合物12g提升幅度較大。進一步採用里賓斯基五規則(Lipinski’s rule of 5)檢驗上述類似物,除分子量外,大部份化合物之性質皆符合規則,其中以morphorline修飾結構之化合物12d能明顯降低CLog P值(親脂性)至3.72。在本研究合成之化合物中,以簡單含氮鹼基修飾之化合物3d對北極光激酶抑制性之IC50為46 nM,且相較於主結構化合物,化合物3d之溶解度與CLog P值均較為改善,以里賓斯基五規則檢驗後,各條件均相當符合適藥性(drug-likeness),目前已交由動物試驗部門做進一步的檢驗,期望能夠發展為新穎北極光激酶抑制劑。

目錄
摘要 I
Abstract II
謝誌 III
縮寫對照表 IV
目錄 VI
表目錄 IX
圖目錄 X
壹、緒論 1
1.1 癌症與化療 1
1.2 北極光激酶抑制劑(Aurora kinase inhibitors) 4
1.2.1 北極光激酶(Aurora kinases) 4
1.2.2 北極光激酶抑制劑之介紹 7
1.2.3 開發北極光激酶抑制劑之沿革 8
貳、研究構想 12
2.1 化合物[E]之最佳化設計 13
2.2 合成設計 14
2.3 溶解度分析 15
參、結果與討論 17
3.1 噁唑并嘧啶系列化合物之合成探討 18
3.2 噁唑并嘧啶系列化合物之結構與活性的探討 24
3.2.1 結構修飾 24
3.2.2 鹽酸鹽型式複合物 30
3.3 噁唑并嘧啶系列化合物之結構與溶解度的探討 31
3.4 綜合討論 33
肆、總結 37
伍、實驗部分 39
5.1 一般實驗方法 39
5.2 噁唑并嘧啶系列化合物之合成步驟與光譜資料 41
5.2.1 化合物3a 之合成 41
5.2.2 化合物3b 之合成 42
5.2.3 化合物3c 之合成 42
5.2.4 化合物3d 之合成 43
5.2.5 化合物7a 之合成 43
5.2.6 化合物7b 之合成 44
5.2.7 化合物7c 之合成 44
5.2.8 化合物7d 之合成 45
5.2.9 化合物8a 之合成 45
5.2.10 化合物8b 之合成 46
5.2.11 化合物8c 之合成 47
5.2.12 化合物8d 之合成 48
5.2.13 化合物8e 之合成 48
5.2.14 化合物8f 之合成 49
5.2.15 化合物8g 之合成 49
5.2.16 化合物8h 之合成 50
5.2.17 化合物9 之合成 51
5.2.18 化合物12a 之合成 51
5.2.19 化合物12b 之合成 53
5.2.20 化合物12c 之合成 53
5.2.21 化合物12d 之合成 54
5.2.22 化合物12e 之合成 55
5.2.26 化合物12f 之合成 55
5.2.23 化合物12g 之合成 56
5.2.24 化合物12h 之合成 56
5.2.25 化合物12i 之合成 57
陸、參考資料 58
附錄一 核磁共振譜資料 63
附錄二 化合物編號對照表 83
陸、參考資料
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