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研究生： 蔡明宗
Tsai, Ming-Tsung
論文名稱： 壹：開發新穎北極光激酶抑制劑於抗癌藥物之研究 貳：設計與合成新穎自溶酵素S抑制劑於抗癌症轉移之應用
I. Discovery of Novel Aurora Kinase Inhibitors as Anticancer Agents ; II. Design and Synthesis of Novel Cathepsin S Inhibitors Against Cancer Metastasis
指導教授： 汪炳鈞
Uang, Biing-Jiun
謝興邦
Hsieh, Hsing-Pang
口試委員:
學位類別： 博士
Doctor
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2009
畢業學年度： 98
語文別： 中文
論文頁數： 534
中文關鍵詞： 北極光激酶 、抗癌藥物 、自溶酵素 S 、癌症轉移
外文關鍵詞： Aurora kinase, anti-cancer drug, Cathepsin S, Metastasis
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    • 本論文包含兩個部分
    第壹部分：開發新穎北極光激酶抑制劑於抗癌藥物之研究

    利用次結構（sub-structure）進行小分子化合物庫的搜尋，找到了以呋喃[2,3-d]嘧啶為核心結構的化合物I-48，其具有不錯的北極光激酶抑制效果，伴隨著含脲側鏈之化合物I-197的發現與人類直腸結腸癌細胞株（HCT-116）生長抑制活性的展現之後。透過合成方法的建立，藉此瞭解化合物I-48與I-197的呋喃[2,3-d]嘧啶之5號及6號位置之結構與活性關係（SAR），經由許多結構的修飾來增進活性與類藥性質，總共合成了67個衍生物。
    化合物類藥性質的改善策略為：將極性基團引入5號苯環，如化合物I-225；將氫原子、氯原子與羥基丁基取代5號苯環，如化合物I-214、I-216與I-225與將結構簡化且核心結構改變，如化合物I-229與I-239d，其中化合物I-225對於北極光激酶A的IC50為21 nM，且能在26 nM濃度下引起四倍體DNA積聚現象。透過核心結構的修飾能有效提升藥物的藥效性質，同時提升化合物抑制癌細胞生長的能力，使得這類五-六駢環雜環在抗癌藥物的開發上更具有發展潛力。

    第貳部分：設計與合成新穎自溶酵素S抑制劑於抗癌症轉移之應用

    目前有越來越多證據指出自溶酵素S（CTSS）與癌轉移之間的關連性，透過CTSS抑制劑的開發，並挑選出活性不錯的化合物進行抗癌症轉移的相關活性測試，希望可以瞭解CTSS與癌症轉移的關連且同時發展抗癌症轉移的藥物。
    由文獻報導知道CTSS抑制劑的結構特徵為胜肽或胜肽類衍生物，藉由親電子性彈頭，如醛基或腈基引入抑制劑的P1端，能有效增進CTSS的抑制活性。因此，合成了17個二胜肽類CTSS抑制劑來進行結構與活性關係的探討，其中，以醛基為彈頭的化合物II-63具有相當不錯的CTSS抑制活性（IC50 = 2 nM），而化合物II-63的差向異購物（化合物II-82，IC50 = 2506 nM）活性下降了1000倍，表示抑制劑的掌性中心是很重要的。此外，將P1端彈頭固定為腈基，P3端為脲基團或硫脲基團連結之化合物II-91a與II-91b亦被合成出來。具有不錯CTSS抑制活性的化合物II-63更進一步的進行抑制腫瘤生長、遷徙與侵襲效果之評估，與抑制基質裂解的實驗結果將於此處進行討論。

    目錄 中文摘要 i 英文摘要 iii 謝誌 v 目錄 vi 圖目錄 xii 表目錄 xvi 流程目錄 xviii 縮寫對照表 xxi 第壹部份：開發新穎北極光激酶抑制劑於抗癌藥物之研究 第一章、緒論 1 1.1 前言 1 1.2 抗癌藥物的分類 3 1.2.1 烷化劑（Alkylation agents） 3 1.2.2 DNA凹槽結合試劑 4 1.2.3 DNA嵌入劑（Intercalating agent） 4 1.2.4 DNA拓樸酶抑制劑（Topoisomerases inhibitor） 5 1.2.5 DNA切割試劑（DNA strand cutters） 5 1.2.6 抗代謝與核酸類試劑（Antimetabolites and nucleoside analogs） 6 1.2.7 微管蛋白抑制劑（Microtubule inhibitor） 7 1.2.8 荷爾蒙拮抗劑（Hormone antagonist） 8 1.2.9 免疫療法（Immunotherpy） 8 1.2.10 基因療法 9 1.2.11 激酶抑制劑（kinase inhibitors） 9 1.2.12 血管新生抑制劑（angiogenesis inhibitor） 10 1.2.13 其他 11 1.3 蛋白質激酶 12 1.3.1 激酶的結構與功能 13 1.3.2 人類kinome 15 1.4 以激酶為標靶的上市藥物 16 1.5 激酶與細胞週期（Cell cycle） 18 1.6 北極光激酶（Aurora kinases） 19 1.6.1 北極光激酶的介紹 19 1.6.2 北極光激酶與有絲分裂（Mitosis） 21 1.6.3 北極光激酶與癌症 25 1.7 北極光激酶抑制劑之發展近況 28 1.7.1 嘧啶類北極光激酶抑制劑 29 1.7.2 嘧啶騈環類北極光激酶抑制劑 33 1.7.3 吡唑類北極光激酶抑制劑 36 第二章、研究構想 39 2.1 發展北極光激酶抑制劑的團隊與分工合作 40 2.1.1 北極光激酶A抑制活性的測試原理 41 2.1.2 HCT-116大腸直腸癌細胞的活性測試原理 42 2.1.3 四倍體DNA積聚（4N DNA accumulation）實驗 43 2.2 化合物I-48的最佳化策略 44 2.2.1 先導藥物之確認及其相關資訊 44 2.2.2 先導藥物（I-48）之最佳化策略 45 2.3 文獻回顧：以五員雜環并嘧啶為骨架之合成與研究 46 2.3.1 5,6-苯環雙取代呋喃[2,3-d]嘧啶之相關合成 47 2.3.2 5-或6-單苯環取代之呋喃[2,3-d]嘧啶衍生物的合成 48 2.3.3 5,6-無取代呋喃[2,3-d]嘧啶之相關合成 52 2.3.4 呋喃[2,3-d]嘧啶合成機構之探討 54 2.3.5 其他嘧啶類五六胼環 57 第三章、結果與討論 3.1 先導化合物I-48的5號與6號位置 66 3.1.1 6-苯基呋喃[2,3-d]嘧啶之合成 66 3.1.2 5-苯基呋喃[2,3-d]嘧啶之合成 69 3.1.3 側鏈的引入與結構鑑定 70 3.1.4 呋喃[2,3-d]嘧啶衍生物之5號與6號位置之結構與活性關係 72 3.1.5 5,6-雙取代呋喃[2,3-d]嘧啶衍生物之合成與結構與活性關係 73 3.1.6 利用交聯耦合反應（cross coupling）探討5號位置 75 3.1.7 化合物I-48之細胞活性測試與最佳化方向 80 3.1.8 芳香雜環與極性基團的引入 83 3.1.9 脂肪族引入呋喃[2,3-d]嘧啶之5號位置 85 3.1.10 羧酸引入呋喃[2,3-d]嘧啶之5號位置 91 3.2 含脲側鏈的發現與細胞抑制活性的顯現 94 3.2.1 尋找適合呋喃[2,3-d]嘧啶之側鏈的策略 94 3.2.2 類藥性質：Lipinski’s rule of five 97 3.3 改善化合物I-197之類藥性質 98 3.3.1 極性官能基團引入之合成研究 98 3.3.2 極性官能基團引入之結構與活性關係 103 3.3.3 化合物I-207a與VX-680（I-38）的比較 105 3.4 化合物I-197之5號與6號苯環的必要性 106 3.4.1 核心結構的修飾 107 3.4.2 化合物I-197之5號與6號苯環必要性的探討 108 3.5 脂肪族引入呋喃[2,3-d]嘧啶5號位置 109 3.5.1 醇基與酯基的引入 109 3.5.2 甲基與炔基的引入 110 3.5.3 脂肪族引入呋喃[2,3-d]嘧啶5號位置之結構與活性分析 112 3.6 核心結構的改變 115 3.6.1 呋喃[3,2-d]嘧啶 115 3.6.2 呋喃[3,2-d]嘧啶之合成 115 3.6.3 以噁唑[5,4-d]嘧啶為核心結構 117 3.6.4 噁唑[5,4-d]嘧啶之合成 118 3.7 呋喃[3,2-d]嘧啶與噁唑[5,4-d]嘧啶為核心結構之結構與活性關係 120 3.7.1 呋喃[3,2-d]嘧啶 120 3.7.2 呋喃[3,2-d]嘧啶與噁唑[5,4-d]嘧啶 121 3.8 結論 124 第貳部份：設計與合成新穎自溶酵素S抑制劑於抗癌症轉移之應用 第四章、緒論 127 4.1 前言 127 4.1.1 癌細胞的轉移與蛋白質水解 127 4.2 蛋白酶的分類及功能 133 4.2.1 蛋白酶的分類與催化機制 133 4.2.2 半胱胺酸自溶酵素蛋白酶 135 4.3 自溶酵素S抑制劑 140 4.3.1 自溶酵素S抑制劑的設計原理 140 4.3.2 自溶酵素S抑制劑的類型 141 4.4 研究動機 156 第五章、結果與討論 158 5.1 非共價性二胜肽類化合物 158 5.1.1 二胜肽化合物II-37的逆合成分析 158 5.1.2 二胜肽化合物II-37的合成 159 5.1.3 化合物II-37衍生物的合成 162 5.1.4 二胜肽化合物的CTSS活性 165 5.2 二胜肽醛及彈頭的改變 167 5.2.1 CTSS抑制劑的循理性設計（rational-design） 167 5.2.2 二胜肽醛及其衍生物之合成 168 5.2.3 化合物II-63及其衍生物之結構活性關係 172 5.2.4 二胜肽醛II-63及其差向異構物II-81 173 5.2.5 CTSS抑制劑P3位置的探討 174 5.3 抑制癌細胞遷移與侵襲的效果及後續發展 179 5.3.1 化合物II-63的細胞毒性測試 179 5.3.2 化合物II-63對於抗癌細胞轉移與侵襲的效果 179 5.3.3 化合物II-63抑制細胞外間質降解的效果 182 5.3.4 化合物II-63之後續發展 183 5.4 結論 185 第六章 實驗部分 1.1 一般實驗方法 187 1.2 第壹部份化合物之實驗步驟與光譜資料 190 1.3 第壹部份化合物之實驗步驟與光譜資料 308 第七章 參考文獻 345 附錄一 化合物之氫核磁共振光譜 360 附錄二 化合物編號對照表 486 附錄三 生物活性測試方法 491 附錄四 論文口試投影片 497

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