開發新穎EGFR激酶抑制劑於抗癌藥物之研究｜國立清華大學博碩士論文庫

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研究生：	吳佳憲 Wu, Chia-Hsien
論文名稱：	開發新穎EGFR激酶抑制劑於抗癌藥物之研究 Discovery of Novel EGFR Kinase Inhibitors as Anticancer Agents
指導教授：	廖俊臣 Liao, Chun-Chen 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：	2010
畢業學年度：	99
語文別：	中文
論文頁數：	327
中文關鍵詞：	上皮生長因子受器、激酶抑制劑、非小細胞肺癌
外文關鍵詞：	EGFR, kinase inhibitor, NSCLC
相關次數：	點閱：2 下載：0
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肺癌是當前對人類的健康和生命最具威脅的惡性腫瘤，其中非小
細胞肺癌 (NSCLC)佔了約80% ~ 85%。研究顯示上皮生長因子受器
(EGFR)的過量表現和NSCLC 之間有相當密切的關連。EGFR 為一膜
蛋白，包含了膜外的配體 (ligand)結合受器及膜內的酪胺酸激酶
(tyrosine kinase)。愛瑞莎 (Iressa)和得舒緩 (Tarceva)是兩個通過美國
FDA 的NSCLC 上市藥物，藉由和三磷酸腺苷 (ATP)競爭EGFR 激酶
的活性位置來抑制激酶的活性。但服用愛瑞莎或得舒緩顯現療效的病
患，平均6–12 個月即會產生抗藥性，其中約50%的病患是因為單點
突變 (T790M)造成抗藥性，而使藥物失去效用，因此我們的目標是
發展兼具有一般EGFR 及突變EGFR 激酶抑制活性的化合物，期望在
將來對有抗藥性的病患能提供一個更佳的治療方法。
藉由混成設計(hybrid design)及循理性設計(knowledge-based
design)，引入具有立體中心的(S)-phenyl-glycinol 及Michael acceptor
至高通量細胞篩選所獲得出的先導化合物43 中，得到一系列化合物
135，150，175 及178，對EGFR 激酶酵素及EGFR 過度表現的HCC827
肺癌細胞株皆具有1~9 nM 抑制活性，且對愛瑞莎抗藥性的雙突變
EGFR (T790M/L858R)激酶酵素也有10~305 nM 的抑制效果。在結構
與活性的研究中得知，具有立體中心的(S)-phenyl-glycinol 及Michael
acceptor 在抑制EGFR 激酶活性上皆是不可或缺的重要因素，將於論
文中詳述，部分結果已發表於J. Med. Chem. 2010, 53, 7316–7326。

Lung cancer is the first leading cause of death in human cancer, with 80-85% being non-small cell lung cancer (NSCLC). Over-expression of epidermal growth factor receptors (EGFR) is in 40-80% of NSCLC. Gefitinib (Iressa; AstraZeneca Pharmaceuticals) and erlotinib (Tarceva; Genentech, Inc.) were approved by U.S. Food and Drug Administration as EGFR kinase inhibitors for the treatment of adenocarcinoma (subtype of NSCLC). Gefitinib and erlotinib competitively bind to the ATP binding pocket of EGFR tyrosine kinase domain and inhibit its activity. These two drugs showed high response rates in specific subsets of NSCLC patients, but patients become resistant to treatment with gefitinib or erlotinib after 6-12 months. For approximately 50% of patients who respond initially to gefitinib or erlotinib, drug resistance occurs as a result of secondary mutation such as the Thr790 to Met790 (T790M) mutation. We designed and synthesized novel EGFR-TKIs, and expect that we can overcome the resistance issues for potential NSCLC therapy, and developed 2nd generation drugs.
Through hybrid design and knowledge-based design concepts, (S)-phenyl-glycinol and Michael acceptor groups were introduced to high throughput hit 43 to obtain compounds 135, 150, 175 and 178 with 1~9 nM inhibition against wild type EGFR enzyme and EGFR overexpressed HCC827 NSCLC cell-line. This series also showed 10~305 nM inhibition against gefitinib-resistant double mutant EGFR (T790M/L858R) enzyme. More than 150 analogues based on compound 117 were synthesized, presence of (S)-phenyl-glycinol and Michael acceptor groups are essential for activity in this series of compounds and part of the results were published in J. Med. Chem., 2010, 53, 7316–7326.

中文摘要...................................................................................................i
英文摘要................................................................................................ iii
謝誌..........................................................................................................v
目錄.........................................................................................................vi
表目錄.................................................................................................. xiii
圖目錄....................................................................................................xv
流程目錄............................................................................................ xviii
縮寫對照表...........................................................................................xix
第一章、緒 論.......................................................................................1
1 前言.............................................................................................1
2 抗癌藥物的分類........................................................................3
2.1 烷化劑.................................................................................3
2.2 DNA 嵌入劑........................................................................4
2.3 DNA 凹槽結合試劑............................................................4
2.4 DNA 拓撲異構酶抑制劑....................................................5
2.5 DNA 切割試劑....................................................................5
2.6 抗代謝試劑.........................................................................6
2.7 微管蛋白抑制劑劑.............................................................7
2.8 賀爾蒙拮抗劑.....................................................................8
2.9 單株抗體 (蛋白質藥物).....................................................8
2.10 激酶抑制劑.........................................................................9
2.11 其他......................................................................................9
3 蛋白質激酶..............................................................................11
4 激酶標靶藥物........................................................................13
5 上皮生長因子受器（EGFR） ................................................16
6 EGFR 與非小細胞肺癌 (Non-small cell lung cancer) ...........22
7 EGFR 激酶突變與抗藥性.......................................................23
8 EGFR 抑制劑之發展近況 (EGFR TKI).................................26
8.1 可逆型抑制劑 (Reversible inhibitors) .............................26
8.2 非可逆型抑制劑 (Irreversible inhibitors)........................31
第二章、研究構想及方法...................................................................50
1 發展EGFR 激酶抑制劑的團隊分工......................................50
1.1 EGFR 激酶抑制活性的測試............................................53
1.2 HCC827 非小細胞肺癌細胞活性測試原理....................54
2 合成文獻回顧：噻吩并嘧啶化合物之合成與研究..............55
2.1 5,6-無取代噻吩[2,3-d]嘧啶之相關合成..........................56
2.2 5,6-取代噻吩[2,3-d]嘧啶之相關合成..............................57
2.3 5-或6-單苯取代噻吩[2,3-d]嘧啶之合成........................58
2.4 2-胺基噻吩在合成上的應用............................................59
3 吡咯[2,3-d]嘧啶 (pyrrolo[2,3-d]pyrimidine)之合成..............61
4 呋喃[2,3-d]嘧啶 (furo[2,3-d]pyrimidine)之合成...................61
5 研究構想..................................................................................62
第三章、結果與討論...........................................................................64
1 先導化合物的最佳化修飾......................................................64
1.1 5,6,7,8-四氫苯并[4,5]噻吩[2,3-d]嘧啶之合成................64
1.2 4-氮-噻吩[2,3-d]嘧啶化合物之修飾................................65
2 循理性設計 (Knowledge-Based Design) ..............................69
2.1 Gefitinib 相似物之合成....................................................69
2.2 Lapatinib 相似物之合成...................................................71
2.2.1 Lapatinib 支鏈的引入及化合物112 的合成...................71
2.2.2 化合物112 之細胞活性測試..........................................72
3 混成設計 (Hybrid design).......................................................74
3.1 化合物117 的設計............................................................74
3.2 化合物117 之脂肪族取代衍生物...................................76
3.3 化合物117 引入羧基及酯基結構與活性比較...............77
4 麥可受體 (Michael acceptor)的引入與活性探討..................79
4.1 化合物135 的合成...........................................................79
4.2 氨基引入化合物135 之研究—化合物150 的合成.......82
4.3 化合物150 變溫核磁共振實驗.......................................84
4.4 化合物150 衍生物之合成...............................................90
4.5 苯甘胺醇碳鏈長度變化對活性影響...............................91
4.6 化合物161 及衍生物設計...............................................92
5 麥可受體 (Michael acceptor)的引入與活性探討..................95
6 氧-烷基化 (O-alkylation)對活性改變的探討........................98
7 芐基間位氟取代的引入..........................................................99
8 芐基取代及雜環的引入........................................................101
9 藥物動力學與動物實驗的探討............................................102
10 化合物135 藥物動力學的改善策略..................................106
11 化合物200 及201 的發展..................................................110
12 結論.......................................................................................111
第四章、實驗部份.............................................................................114
1 一般實驗方法...........................................................................114
2 實驗步驟與光譜資料..............................................................117
2.1 化合物43 的合成.........................................................117
2.2 化合物84 的合成.........................................................117
2.3 化合物85 的合成.........................................................118
2.4 化合物86 的合成.........................................................119
2.5 化合物88 的合成.........................................................120
2.6 化合物89 的合成.........................................................120
2.7 化合物90 的合成.........................................................121
2.8 化合物91 的合成.........................................................122
2.9 化合物92 的合成.........................................................123
2.10 化合物93 的合成.........................................................124
2.11 化合物94 的合成.........................................................125
2.12 化合物95 的合成.........................................................126
2.13 化合物96 的合成.........................................................127
2.14 化合物97 的合成.........................................................128
2.15 化合物98 的合成.........................................................129
2.16 化合物99 的合成.........................................................130
2.17 化合物100 的合成.......................................................131
2.18 化合物101 的合成.......................................................132
2.19 化合物102 的合成.......................................................132
2.20 化合物103 的合成.......................................................133
2.21 化合物104 的合成.......................................................134
2.22 化合物105 的合成.......................................................135
2.23 化合物106 的合成.......................................................136
2.24 化合物107 的合成.......................................................137
2.25 化合物112 的合成........................................................138
2.26 化合物113 的合成........................................................139
2.27 化合物114 的合成........................................................140
2.28 化合物115 的合成........................................................141
2.29 化合物116 的合成........................................................142
2.30 化合物117 的合成........................................................143
2.31 化合物119 的合成........................................................144
2.32 化合物120 的合成.......................................................145
2.33 化合物121 的合成.......................................................146
2.34 化合物122 的合成.......................................................147
2.35 化合物123 的合成.......................................................148
2.36 化合物124 的合成.......................................................149
2.37 化合物125 的合成.......................................................150
2.38 化合物126 的合成.......................................................151
2.39 化合物127 的合成.......................................................152
2.40 化合物128 的合成.......................................................153
2.41 化合物129 的合成.......................................................154
2.42 化合物130 的合成.......................................................155
2.43 化合物131 的合成.......................................................156
2.44 化合物132 的合成.......................................................157
2.45 化合物133 的合成.......................................................158
2.46 化合物134 的合成.......................................................159
2.47 化合物135 的合成.......................................................161
2.48 化合物138 的合成.......................................................162
2.49 化合物139 的合成.......................................................163
2.50 化合物140 的合成.......................................................164
2.51 化合物141 的合成.......................................................165
2.52 化合物142 的合成.......................................................165
2.53 化合物143 的合成.......................................................166
2.54 化合物144 的合成.......................................................167
2.55 化合物145 的合成.......................................................168
2.56 化合物146 的合成.......................................................170
2.57 化合物147 的合成.......................................................171
2.58 化合物148 的合成.......................................................172
2.59 化合物149 的合成.......................................................173
2.60 化合物150 的合成.......................................................174
2.61 化合物151 的合成.......................................................176
2.62 化合物152 的合成.......................................................177
2.63 化合物153 的合成.......................................................178
2.64 化合物154 的合成.......................................................179
2.65 化合物161 的合成.......................................................181
2.66 化合物162 的合成.......................................................182
2.67 化合物166 的合成.......................................................183
2.68 化合物167 的合成.......................................................184
2.69 化合物168 的合成.......................................................185
2.70 化合物169 的合成.......................................................186
2.71 化合物171 的合成.......................................................187
2.72 化合物173 的合成.......................................................188
2.73 化合物174 的合成.......................................................190
2.74 化合物179 的合成.......................................................191
2.75 化合物180 的合成.......................................................192
2.76 化合物181 的合成.......................................................193
2.77 化合物193 的合成.......................................................194
2.78 化合物194 的合成.......................................................195
2.79 化合物195 的合成.......................................................196
2.80 化合物196 的合成.......................................................196
2.81 化合物197 的合成.......................................................197
第五章、參考資料.............................................................................199
附錄一 氫核磁共振光譜.................................................................209
附錄二 編號對照表.........................................................................288
附錄三 生物活性測試方法.............................................................292
附錄四 論文口試投影片.................................................................295
附錄五 發表之論文.........................................................................327

                                

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