第壹部份 ： EGFR與c-Met雙重激酶抑制劑之研究
以呋喃嘧啶EGFR抑制劑為核心結構，引入c-Met抑制劑側鏈，設計與合成一系列呋喃嘧啶化合物，並探討其做為EGFR和c-Met雙重功能抑制劑的潛力。本論文以具有麥可受體的EGFRL858R/T790M抑制劑12為核心，於呋喃[2,3-d]嘧啶四號位置上引入不同的c-Met側鏈，找出較適合的雙重抑制劑側鏈，再以循理性藥物設計探討六號位置的取代基大小及異原子對活性的影響，最後發展出具有EGFRL858R/T790M (IC50 = 43 nM)與c-Met (IC50 = 19 nM)雙重激酶抑制效果的化合物35j2。

第貳部分 ： DBPR104磷酸前驅物之合成研究
利用磷酸前驅藥物的設計策略來改善抗癌藥物DBPR104對水溶解度過低 (0.9 μg/mL) 的問題，由於NCH2O鍵的不穩定，在合成上都無法成功地引入磷酸的水溶性基團。

Part I. Development of Dual EGFR and c-Met Kinase Inhibitors
Based on knowledge-based drug design, we hybridized the core structure of EGFR kinase inhibitors and c-Met kinase inhibitors. Also, we designed and synthesized a series of furanopyrimidine compounds as dual-functional inhibitors of EGFR and c-Met kinase, as well as explored their applications. We used compound 12 as core structure, containing a Michael acceptor group, and introduced different c-Met kinase inhibitor side chains at 4-position of furano[2,3-d]pyrimidine to examine the more suitable side chain for dual-functional inhibitor. Followed by rational drug design, we explored the effects of size and heteroatoms of aromatic substitutions at 6-position of furano[2,3-d]pyrimidine on activity. Finally, we discovered the compound 35j2 that possesses EGFRL858R/T790M (IC50 = 43 nM) and c-Met (IC50 = 19 nM) kinase activities as potential dual inhibitor.

Parts II. Development of DBPR104 Phosphate Prodrugs
Because of the properties of anticancer drug DBPR104, we focused on utilizing phosphate prodrugs strategy to improve poor water solubility (0.9 μg/mL). Due to the instability of the NCH2O bond of the DBPR104 structure, the synthesis by introducing phosphate groups into DBPR104 and compound 62 faced difficulty.

中文摘要......................................................................i
英文摘要......................................................................ii
謝誌...........................................................................iii
目錄...........................................................................iv
圖目錄.........................................................................xi
表目錄......................................................................xiii
式目錄......................................................................xiv
縮寫對照表.................................................................xv
第壹部份 : EGFR 與 c-Met 雙重激酶抑制劑之研究
第一章、 緒論...............................................................1
1.1 前言................................................................1
1.2 肺癌................................................................3
1.2.1 小細胞肺癌................................................4
1.2.2 非小細胞肺癌.............................................4
1.3 蛋白質激酶(Protein kinase)....................................6
1.4 表皮生長因子受器..............................................8
1.4.1 EGFR 結構..................................................8
1.4.2 EGFR 訊息傳遞路徑......................................9
1.5 EGFR 激酶突變................................................11
1.6 EGFR 激酶抗藥性.............................................12
1.7 EGFR 激酶抑制劑簡介.......................................14
1.7.1 單株抗體藥物............................................14
1.7.2 小分子EGFR抑制劑...................................15
1.8 c-Met(絡氨酸蛋白激酶Met).................................19
1.9 c-Met 放大與非小細胞肺癌.................................20
1.10 c-Met激酶抑制劑簡介.......................................21
1.10.1 c-Met激酶抑制劑classI..............................22
1.10.2 c-Met激酶抑制劑classII.............................23
1.11EGFR與c-Met 雙重激酶抑制劑............................25
第二章、 研究動機........................................................26
2.1 臨床上使用 EGFR 激酶抑制劑聯合 c-Met 激酶抑制劑之困難....26
2.2 EGFR 激酶抑制劑研究開發歷程............................27
2.3 研究構想.........................................................29
2.4 EGFR與c-Met酪氨酸激酶抑制劑活性測試法..............32
2.4.1 EGFR 絡氨酸激酶抑制劑活性測試法.................32
2.4.2 c-Met 絡氨酸激酶抑制劑活性測試法..................32
2.5 人類非小細胞肺癌細胞株(H1975)與人類表皮癌細胞株 (A431)生長抑制測試...33
第三章、 結果與討論.....................................................35
3.1 呋喃[2,3-d]嘧啶核心結構合成..............................35
3.2 c-Met 側鏈置換.................................................36
3.2.1 c-Met 側鏈合成............................................36
3.2.2 置換c-Met側鏈b與c...................................38
3.2.3 置換 c-Met 側鏈 a’、b’與 c’...............................40
3.3 化合物16異原子六員芳香環的置換.......................43
3.3.1 合成步驟之改善.........................................43
3.3.2 含氮六員芳香環置換...................................44
3.3.3 化合物16苯環上引入水溶性基團...................46
3.4 化合物 16 異原子五員芳香環的置換.......................47
3.4.1 化合物 35j2 c-Met 側鏈置換...........................50
3.5 H1975與A431細胞活性測試................................52
3.6 多靶點激酶抑制活性分析....................................54
3.7 化合物35j2之藥物動力學分析..............................57
第四章、 總結..............................................................60
第貳部分 : DBPR104 磷酸前驅物之合成研究
第五章、 DBPR104 磷酸前驅物之合成研究........................65
5.1 抗癌藥物 DBPR104 之簡介..................................65
5.2 前驅藥物之簡介................................................68
5.2.1 磷酸前驅藥物.............................................68
5.2.2 吲哚類前驅藥物..........................................70
5.2.3 7-氮雜吲哚前驅藥物......................................70
5.3 研究動機.........................................................72
5.4 磷酸前驅物之合成.............................................73
5.4.1 7-氮雜吲哚化合物 62 之合成..........................73
5.4.2 化合物 62 引入 di-t-butyl(chlorpomethyl) phosphate...74
5.4.3 DBPR104 引入 di-t-butyl(chlorpomethyl) phosphate...74
5.4.4 保護基水解................................................74
5.4.5 化合物 62 引入 dibenzyl(chloromethyl) phosphate..75
5.5 結論...............................................................77
第六章、 實驗部分........................................................78
6.1 一般實驗方法...................................................78
6.2 化合物之實驗步驟與光譜資料..............................80
6.2.1 化合物 18 之合成.........................................80
6.2.2 化合物 19 之合成.........................................80
6.2.3 化合物 20 之合成.........................................81
6.2.4 化合物 21 之合成.........................................82
6.2.5 化合物 22 之合成.........................................82
6.2.6 化合物 23 之合成.........................................83
6.2.7 化合物 25 之合成.........................................84
6.2.8 化合物 27 之合成.........................................84
6.2.9 化合物 29 之合成.........................................85
6.2.10 化合物30之合成.......................................86
6.2.11 化合物31之合成.......................................87
6.2.12 化合物32之合成.......................................88
6.2.13 化合物32b之合成.....................................89
6.2.14 化合物32b1之合成....................................90
6.2.15 化合物32b2之合成....................................91
6.2.16 化合物 32c 之合成.....................................92
6.2.17 化合物 32c1 之合成....................................93
6.2.18 化合物 32c2 之合成....................................94
6.2.19 化合物33之合成.......................................95
6.2.20 化合物33a之合成.....................................96
6.2.21 化合物33a1之合成....................................97
6.2.22 化合物33a2之合成....................................97
6.2.23 化合物33b之合成.....................................99
6.2.24 化合物33b1之合成....................................99
6.2.25 化合物33b2之合成..................................100
6.2.26 化合物 33c 之合成....................................101
6.2.27 化合物 33c1 之合成..................................102
6.2.28 化合物 33c2 之合成..................................103
6.2.29 化合物34之合成.....................................104
6.2.30 化合物35之合成.....................................105
6.2.31 化合物35a之合成....................................106
6.2.32 化合物35a1之合成..................................107
6.2.33 化合物35a2之合成..................................108
6.2.34 化合物35b之合成....................................109
6.2.35 化合物35b1之合成..................................110
6.2.36 化合物35b2之合成..................................111
6.2.37 化合物 35c 之合成....................................112
6.2.38 化合物 35c1 之合成..................................113
6.2.39 化合物 35c2 之合成..................................113
6.2.40 化合物35d之合成....................................115
6.2.41 化合物35d1之合成..................................115
6.2.42 化合物35d2之合成..................................116
6.2.43 化合物 35e 之合成....................................118
6.2.44 化合物 35e1 之合成..................................119
6.2.45 化合物 35e2 之合成..................................119
6.2.46 化合物35f之合成....................................121
6.2.47 化合物35f1之合成...................................122
6.2.48 化合物35f2之合成...................................122
6.2.49 化合物35g之合成....................................124
6.2.50 化合物35g1之合成..................................124
6.2.51 化合物35g2之合成..................................125
6.2.52 化合物35h之合成....................................126
6.2.53 化合物35h1之合成..................................127
6.2.54 化合物35h2之合成..................................128
6.2.55 化合物35i之合成....................................129
6.2.56 化合物35i1之合成...................................130
6.2.57 化合物35i2之合成...................................131
6.2.58 化合物35j之合成....................................132
6.2.59 化合物35j1之合成...................................133
6.2.60 化合物35j2之合成...................................134
6.2.61 化合物36之合成.....................................135
6.2.62 化合物36b之合成....................................136
6.2.63 化合物36b1之合成..................................137
6.2.64 化合物36b2之合成..................................138
6.2.65 化合物 36c 之合成....................................139
6.2.66 化合物 36c1 之合成..................................140
6.2.67 化合物 36c2 之合成..................................141
6.2.68 化合物35k之合成....................................142
6.2.69 化合物35k1之合成..................................143
6.2.70 化合物35k2之合成..................................144
6.2.71 化合物35k3之合成..................................145
6.2.72 化合物58之合成.....................................146
6.2.73 化合物59之合成.....................................146
6.2.74 化合物60之合成.....................................147
6.2.75 化合物61之合成.....................................148
6.2.76 化合物62之合成.....................................148
6.2.77 化合物63之合成.....................................149
6.2.78 化合物54之合成.....................................150
第七章、 參考資料......................................................151
附錄一、化合物編號對照表.....................................156
附錄二、核磁共振光譜資料.....................................159
附錄三、口試投影片..............................................255
圖目錄
圖一 肺癌分類..............................................................3
圖二 激酶磷酸化示意圖...................................................6
圖三 ATP 與激酶結合示意圖.............................................7
圖四 EGFR 結構示意圖...................................................9
圖五 EGFR 激酶活化示意圖.............................................9
圖六 EGFR 訊息傳遞路徑...............................................10
圖七 亞洲與歐美人非小細胞肺癌突變比例.........................11
圖八 EGFR 突變位置示意圖............................................12
圖九 EGFR 抗藥性比例..................................................13
圖十 T790M 示意圖......................................................13
圖十一 Gefitinib結構式.....................................................15
圖十二 Erlotinib結構式.....................................................16
圖十三 Afatinib 結構式.....................................................16
圖十四 Osimertinib 結構式.................................................17
圖十五 Olmutinib 結構式...................................................18
圖十六 c-Met 結構...........................................................20
圖十七 MET 基因放大活化 ERBB3 示意圖.............................21
圖十八 DFG-in與DFG-out示意圖.......................................22
圖十九 Crizotinib結構式...................................................22
圖二十 Cabozantinib結構式................................................23
圖二十一 MGCD265 結構式.............................................23
圖二十二 BMS-777607 結構式..........................................24
圖二十三 化合物 9 結構式................................................25
圖二十四 化合物 10 引入麥可接受器流程示意圖...................28
圖二十五 化合物 12 置換 c-Met 側鏈流程示意圖....................29
圖二十六 c-Met 側鏈......................................................31
圖二十七 激酶抑制劑測試原理.........................................33
圖二十八 MTS 測試原理.................................................34
圖二十九 EGFR 與 c-Met 雙重激酶抑制劑合成優化流程............43
圖三十 藥物動力學示意圖............................................58
圖三十一 化合物 35j2 開發之過程......................................60
圖三十二 c-Met 側鏈活性比較..........................................61
圖三十三 EGFRT790M/L858R 激酶抑制活性比較........................62
圖三十四 c-Met 激酶抑制活性比較....................................62
圖三十五 雙重激酶抑制劑合成路徑...................................63
圖三十六 PD154075 之前驅藥物化學結構設計.....................70
圖三十七 Vemurafenib 之前驅藥物化學結構設計..................71
圖三十八 BMS-448043 之前驅藥物化學結構設計..................71
圖三十九 化合物 55 之 Gaussian 09 理論計算結果..................73
表目錄
表一 民國 105 年台灣地區十大死因....................................1
表二 EGFR 在癌症中過度表現比例....................................6
表三 單株抗體藥物......................................................14
表四 化合物 13-16 EGFR 與 c-Met 激酶抑制活性...................30
表五 化合物 32b-c EGFR 與 c-Met 激酶抑制活性...................40
表六 化合物 33a-c EGFR 與 c-Met 激酶抑制活性...................42
表七 化合物 35a-c EGFR 與 c-Met 激酶抑制活性...................45
表八 化合物 35d-e EGFR 與 c-Met 激酶抑制活性...................46
表九 化合物 35f-j EGFR 與 c-Met 激酶抑制活性....................49
表十 1-甲基-1H-咪唑-2-硼酸頻哪醇酯之合成......................50
表十一 化合物36b-cEGFR與c-Met激酶抑制活性...................51
表十二 化合物H1975與A431細胞抑制活性...........................53
表十三 化合物 35j2 之多點激酶抑制活性測試........................54
表十四 激酶相關疾病......................................................56
表十五 化合物35j2、16與osimertinib之藥物動力學性質............59
表十六 DBPR104 之細胞活性與藥物動力學數據.....................66
表十七 改善對水溶解度之前驅藥物....................................69
表十八 化合物 54 去保護基之結果.......................................75
表十九 化合物62引入dibenzyl(chloromethyl)phosphate之結果...76
式目錄
式一 呋喃[2,3-d]嘧啶結構合成..........................................36
式二 化合物 25 側鏈 a 之合成..........................................37
式三 化合物 27 側鏈 b 之合成..........................................37
式四 化合物 30 側鏈 c 之合成..........................................38
式五 化合物 32b2 之合成................................................38
式六 化合物 32c2 之合成................................................39
式七 化合物 33a2 之合成................................................41
式八 化合物 35 之合成...................................................44
式九 呋喃[2,3-d]嘧啶 6 號位置引入鄰位吡啶.......................45
式十 化合物 35i1 之合成................................................48
式十一 呋喃[2,3-d]嘧啶 6 號位置引入 2 號位噻吩.....................48
式十二 化合物 36 之合成...................................................51
式十三 化合物 35k3 之合成..................................................52
式十四 磷酸前驅物之合成路徑一.......................................72
式十五 7-氮雜吲哚之化合物 62 合成....................................73
式十六 7-氮雜吲哚磷酸化合物 63 之合成..............................74
式十七 DBPR104 磷酸化合物之合成....................................74
式十八 磷酸前驅物之合成路徑二.......................................76

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