微管在細胞分裂過程中扮演相當重要的角色，被認為抗癌藥物重要的標靶，而喹啉類化合物是相當具有藥理活性的化合物，從這些抑制微管聚合的抗癌藥物，如：combretastatin A-4、AVE-8062、colchicine與ABT-751的結構上發現，3,4,5-三甲氧基苯基/3,4,5-三甲氧基苯醯基與對位甲氧基苯基對於抗癌活性扮演相當重要的角色，因此，本論文探討喹啉與3,4,5-三甲氧基苯醯基結合作為微管抑制劑之設計與合成。
合成出2-,3-,4-,5-,6-,7-,8-芳醯基喹啉化合物（240，241，242，243，244，245，246），並對人類五種癌細胞（包括口腔上皮細胞癌細胞、非小細胞肺癌細胞H460、結腸直腸癌細胞、胃癌細胞和多重抗藥性癌細胞KB-vin10）進行藥理實驗，結果發現：3,4,5-三甲氧基苯醯基位於喹啉之C-2位與C-6位的2-芳醯基喹啉（240）與6-芳醯基喹啉（244）具有抗癌活性，對人類五種癌細胞的平均IC50分別為172.8與24.4 nM；從CA-4之B環與ABT-751之3-苯基磺胺結構上發現：對位甲氧基對於抗癌活性的重要性，因此，我們將甲氧基導入芳醯基喹啉，得到6-甲氧基-2-芳醯基喹啉（247），其抗癌活性平均為67 nM，為了改善2-芳醯基喹啉的極性與抗癌活性，在喹啉的C-5位導入胺基與羥基，分別得到5-胺基-2-芳醯基喹啉（252）與5-羥基-2-芳醯基喹啉（253），化合物252對人類五種癌細胞的平均IC50分別為0.32 nM，比CA-4抗癌活性(IC50 = 1.9 - 835 nM)更強，化合物253對人類口腔上皮細胞癌細胞的IC50為2.8 nM；接著，喹啉的C-5位再導入不同取代基（如:苯基、拉電子基），其中5-氯基-6-甲氧基-2-苯醯基喹啉、5-氰基-6-甲氧基-2-苯醯基喹啉與5-乙炔基-6-甲氧基-2-苯醯基喹啉對人類口腔上皮細胞癌細胞活性最佳，抗癌活性分別為53、17、38 nM。
將化合物252的羰基以醚基、硫基或硫醯基取代，其中5-胺基-6-甲氧基-2-(3’,4’,5’-三甲氧基苯氧基)喹啉（254）、5-胺基-6-甲氧基-2-(3’,4’,5’-三甲氧基苯硫基)喹啉（256）與5-胺基-6-甲氧基-2-(3’,4’,5’-三甲氧基苯硫醯基)喹啉（257）對人類口腔上皮細胞癌細胞活性最佳，抗癌活性分別為31、59、18 nM。再將苯環上三甲氧基移至喹啉的C-5,6,7位或C-6,7,8位，抗癌活性明顯喪失，2-[(4’-N,N-雙甲基胺基)苯醯基]-6,7,8-三甲氧基喹啉（278）則具有微弱抗癌活性，抗癌活性為217 nM。
在抑制微管聚合試驗，化合物252抑制微管聚合能力(IC50 = 1.6 μM)比combretastatin A-4的抑制微管聚合能力(IC50 = 2.1 μM)更佳，另外在與秋水仙素競爭的試驗中，化合物252與微管之秋水仙素結合處有很強的結合力，因此，本篇論文設計與合成出一系列芳醯基喹啉與苯基喹啉類化合物為一新穎骨架的強微管聚合抑制劑。

Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for anticancer therapy. The quinolines is a pharmacologically active class of heterocyclic compounds. Analysis of these microtubule inhibitors, such as combretastatin A-4、AVE-8062、colchicine and ABT-751 indicates that the 3,4,5-trimethoxyphenyl/3,4,5-trimethoxybenzoyl and para-methoxyphenyl groups seem to play an important role in their bioactivity. Here we report our attempt to explore the quinoline core coupled with the 3,4,5-trimethoxybenzoyl group as tubulin polymerization inhibitors.
The regioisomers 2-, 3-, 4-, 5-, 6-, 7-, and 8-aroylquinolines (240, 241, 242, 243, 244, 245, and 246, respectively) were evaluated for antiproliferative activity against five human cancer cell lines. The 3,4,5-trimethoxybenzoyl group located at the C-2 and C-6 position on quinoline ring resulted in the most potent activity with 2-aroylquinoline (240) and 6-aroylquinoline (244) showing mean IC50 values of 172.8 and 24.4 nM against five cancer cell lines, respectively. The p-methoxy group substitution in the ring-B of CA-4 and in the 3-benzenesulfonamide of ABT-751 are important for activity. Thus, we studied the effect of the addition of the methoxy group in aroylquinolines. 2-Aroyl-6-methoxyquinoline (247) showed substantial antiproliferative activity against five cancer cell lines with mean IC50 values of 67 nM. In an effort to increase the 2-aroylquinolines skeleton’s polarity and activity, the 5-amino-substituted 2-aroylquinoline (252) and 5-hydroxy-substituted 2-aroylquinoline (253) were synthesized. Compound 252 exhibited a mean IC50 value of 0.32 nM in all five cancer cell lines, thus displaying stronger cytotoxicity than CA-4 (IC50 = 1.9 - 835 nM). Compound 253 exhibited a mean IC50 value of 2.8 nM in the KB cell line. Further, we introduced various group at C-5 position of quinoline to give 5-substituted-6-methoxy-2-aroylquinoline. The biological results showed that the 5-chloro, 5-cyano, 5-ethynyl-6-methoxy-2- aroylquinoline (259, 262, 265) with IC50 values of 53, 17 and 38 nM in the KB cell line, respectively.
We replace the carbonyl group of 252 with ether, thio and sulfonyl group. 5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenoxy)quinoline (254)、5-amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenylthio)quinoline (256)、5-amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenylsulfonyl)quinoline (257) showed substantial antiproliferative activity against the KB cell line with IC50 values of 31, 59, and 18 nM, respectively. Shifting of the trimethoxy group of benzene to the C-5, 6, 7 or C-6, 7, 8 position of quinoline resulted in weak cytotoxicity at μM level. 2-[(4’-N,N-dimethylamino)benzoyl]-6,7,8- trimethoxyquinoline (278) showed moderate activity against the KB cell line with IC50 value of 217 nM.
Compound 252 (IC50 = 1.6 μM) exhibited more potent inhibition of tubulin polymerization than combretastatin A-4 (IC50 = 2.1 μM) and showed strong binding property to the colchicine binding site of microtubules. Therefore, we successfully designed and synthesized aroylquinolines and phenylquinolines as novel classes of potent antimitotic agents.

中文摘要...................................................I
英文摘要................................. ...............III
縮寫對照表.................................................V
目錄.....................................................VII
表目錄....................................................XV
圖目錄...................................................XVI
流程目錄..................................................XX

壹、緒論...................................................1
1.1前言....................................................1
1.2抗癌藥物................................................2
1.2.1烷基化藥物............................................2
1.2.2抗代謝藥物............................................4
1.2.3荷爾蒙藥物............................................6
1.2.4拓樸異構酶抑制劑......................................6
1.2.5 微小管抑制劑.........................................8
1.2.6 其他.................................................8
1.3 微小管................................................10
1.3.1 細胞生長週期........................................10
1.3.2 有絲分裂............................................11
1.3.3 微小管的結構與功能..................................12
1.4 作用在微小管的抗癌藥..................................14
1.4.1 微小管去穩定劑......................................14
1.4.2 微小管穩定劑........................................15
1.4.3 抗癌藥Combretastatin A-4（CA-4）之研究進展..........16
1.4.4 Combretastatin A-4 衍生物...........................17
1.5 Combretastatin A-4 類化合物之合成與活性探討...........19
1.5.1 單原子連結..........................................20
1.5.2 雙原子連結..........................................27
1.5.2.1 非環狀連結類化合物................................28
1.5.2.2 非芳香環連結類化合物..............................32
1.5.2.3 雜芳香環連結類化合物..............................34
1.5.2.4 五或六騈環雜環連結類化合物........................38
1.5.3 參原子連結..........................................40
1.5.3.1 1,3-位雜環連結類化合物............................40
1.5.3.2 α,β-不飽合酮連結類化合物.........................42
1.5.4 肆原子連結..........................................45
1.5.5 修飾A環之combretastatin類化合物.....................46
1.5.6 修飾B環之combretastatin類化合物.....................49
1.5.6.1 Substituted phenyl rings..........................49
1.5.6.2 Heterocyclic rings................................52
1.5.6.3 Aromatic rings....................................54
1.5.7 Indoles抗癌化合物之結構和活性關係(SAR)研究..........57
1.5.7.1 2-苯醯基吲哚衍生物................................57
1.5.7.2 1-苯醯基吲哚與3-苯醯基吲哚衍生物..................60
1.5.7.3 4-苯醯基吲哚與5-苯醯基吲哚衍生物..................67
貳、研究構想..............................................68
2.1以quinoline類為主之化合物設計與抗癌活性的研究......68
2.2藥物設計理念.......................................70
2.3合成方法之文獻.....................................75
2.3.1 5,6,7-三甲氧基喹哪啶.........................75
2.3.2 6,7,8-三甲氧基喹哪啶.........................76
2.3.3 6-甲氧基-2-甲基喹唑啉........................77
參、結果與討論............................................78
3.1喹啉類化合物的合成研究.............................78
3.1.1 2-, 3-, 4-, 5-, 6-, 7-, 8-Aroylquinolines逆合成分析.........78
3.1.2 2-, 3-, 4-, 5-, 6-, 7-, 8-Aroylquinolines化合物之合成……….…..79
3.1.3 5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline
逆合成分析………..…………………………………………...87
3.1.4 5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline
化合物之合成………………..………………………………...88
3.1.5 5-Hydroxy-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline
逆合成分析…….……….………………………………………………………………89
3.1.6 5-Hydroxy-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline
化合物之合成…..……………………………...………………90
3.1.7 6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinazoline逆合成分
析……….……………………………………………………………………………………92
3.1.8 6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinazoline化合物之
合成…….………………………………………………………………………………….92
3.1.9 2-Aroylquinoline逆合成分析……………………….…..…………………..93
3.1.10 2-Aroylquinoline化合物之合成………………………….……………….94
3.1.11 6-(3’,4’,5’-Trimethoxybenzoyl)quinoxaline化合物之合成….95
3.1.12 5-Amino-6-methoxyquinoline逆合成分析………..……..…….…..96
3.1.13 5-Amino-6-methoxyquinoline化合物之合成……………..…..…..97
3.1.14 2-Aroyl-5,6,7-trimethoxyquinoline逆合成分析………..…...……98
3.1.15 2-Aroyl-5,6,7-trimethoxyquinoline化合物之合成……......…….99
3.1.16 2-Phenyl-5,6,7-trimethoxyquinoline逆合成分析……………..…100
3.1.17 2-Phenyl-5,6,7-trimethoxyquinoline化合物之成…………….....101
3.1.18 4-Aroyl-6,7,8-trimethoxyquinoline逆合成分析………………..…102
3.1.19 4-Aroyl-6,7,8-trimethoxyquinoline化合物之合成………….…...103
3.2 Quinoline類化合物的抗癌活性研究…………………………………..………..105
3.2.1 2-,3-,4-,5-,6-,7-,8-(3’,4’,5’-Trimethoxybenzoyl)quinolines類化
合物的抗癌活性…………………………………………..….105
3.2.2 6-Methoxy-2-(3’,4’,5’-Trimethoxybenzoyl)quinolines類化合物
的抗癌活性……………………………………………………………………..…....108
3.2.3 5-Amino-6-methoxy-2-phenylquinolines類化合物的抗癌活性
……………………………………………………………………………………………....111
3.2.4 6-Aroylquinoxaline、2-aroylquinazoline、5,6,7-trimethoxy-
quinolines與6,7,8-trimethoxyquinolines類化合物的
抗癌活性…………………………………………………….113
3.3 微管蛋白競爭性試驗………………………………………..…...…115
3.3.1 2-,6-Aroylauinolines類化合物之微管蛋白競爭性試驗……....115
3.4 分子模擬（molecular modeling）試驗…………………………....116
3.4.1化合物252、CA-4與AVE-8063之分子模擬（molecular
modeling）試驗……………………………………………………..116
3.5結論………………………………………………………………….117肆、實驗部分………………………………………………………………...120
4.1一般實驗方法…………………………………………………….…120
4.2 化合物之實驗方法與光譜資料…………………………..……..…123
2-(3’,4’,5’-Trimethoxybenzoyl)quinoline（240）………………..…..123
3-(3’,4’,5’-Trimethoxybenzoyl)quinoline（241）……………….…...123
4-(3’,4’,5’-Trimethoxybenzoyl)quinoline（242）…………………....124
5-(3’,4’,5’-Trimethoxybenzoyl)quinoline（243）…..……………..…125
6-(3’,4’,5’-Trimethoxybenzoyl)quinoline（244）…........................…125
7-(3’,4’,5’-Trimethoxybenzoyl)quinoline（245）……………...….…126
8-(3’,4’,5’-Trimethoxybenzoyl)quinoline（246）………………..…..127
6-Methoxyquinoline-2-carboxaldehyde（290）………………..….…128
6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（247）……..…128
8-Methoxy-4-methylquinoline（300）……………………………..…129
8-Methoxyquinoline-4-carboxaldehyde（301）………...................…130
8-Methoxy-4-(3’,4’,5’-trimethoxybenzoyl)quinoline（248）..........…130
2-Methoxy-6-(3’,4’,5’-trimethoxybenzoyl)quinoline（249）……..…131
6-Methoxy-2-methyl-5-nitroquinoline（289）………………...…..…132
6-Methoxy-5-nitroquinoline-2-carboxaldehyde（291）………………133
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（292）..133
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（252）...
………………………………………………………………………...134
5-Bromo-6-methoxy-2-methylquinoline（294）…………………….135
5-Hydroxy-6-methoxy-2-methylquinoline（306）…………………..135
5-(tert-Butyl-dimethylsilyloxy)-6-methoxyquinoline-2-carbaldehyde
（305）……………...…………………………………………………136
5-Hydroxy-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（253）
……………………………………………………………………..…137
5-Chloro-6-methoxy-2-methylquinoline（293）……………………138
5-Iodo-6-methoxy-2-methylquinoline（295）……………..……....…139
5-Chloro-6-methoxyquinoline-2-carboxaldehyde（296）…………....140
5-Bromo-6-methoxyquinoline-2-carboxaldehyde（297）………….…140
5-Iodo-6-methoxyquinoline-2-carboxaldehyde（298）………………141
5-Chloro-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（259）....
................................................................................................................141
5-Bromo-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（260）
………………………………………………………………………....142
5-Iodo-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（261）…143
5-Cyano-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（262）..143
6-Methoxy-2-(3'',4'',5''-trimethoxybenzoyl)quinoline-5-carboxamide（263）
............................................................................................................…144
5-(3’’-Hydroxy-3’’-methylbut-1’’-ynyl)-6-methoxy-2-(3’,4’,5’-tri- methoxybenzoyl)quinoline（264）……………………………………145
6-Methoxy-2-methyl-5-[(trimethylsilyl)ethynyl]quinoline（303）.....146
6-Methoxy-5-[(trimethylsilyl)ethynyl]quinoline-2-carboxaldehyde（304）
……………...........................................……….…………..…..........…146
5-Ethynyl-6-methoxyquinoline-2-carbaldehyde（302）........………..147
5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（265）
.........................................................................................................…...147
6-Methoxy-5-pyridinyl-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（266）
………………………………………….………..…………………..…148
5-(4’’-Hydroxyphenyl)-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)-
quinoline（267）…………………………..………..………..……..…149
5-(3’,4’-Difluorophenyl)-6-methoxy-2-methylquinoline（314）.....…150
5-(4’-Fluorophenyl)-6-methoxy-2-methylquinoline（315）……...….150
6-Methoxy-2-methyl-5-(4’-nitrophenyl)quinoline（316）.....……..…151
6-Methoxy-2-methyl-5-(4’-methoxyphenyl)quinoline（317）…..…..152
5-(3’,4’-Difluorophenyl )-6-methoxyquinoline-2-carboxaldehyde（309）
……………..……….…………............................................…......…...152
5-(4’-Fluorophenyl )-6-methoxyquinoline-2-carboxaldehyde（310）......
……………………………..………………………………...……..…153
6-Methoxy-5-(4’-nitrophenyl )quinoline-2-carboxaldehyde（311）...154
6-Methoxy-5-(4’-methoxyphenyl )quinoline-2-carboxaldehyde（312）
...............................................................................................................154
5-(3’’,4’’-Difluorophenyl)-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)-
quinoline（268）...................……………..………..………..…….…155
5-(4’’-Fluorophenyl)-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)- quinoline（269）...................……………………………..……….…156
6-Methoxy-5-(4’’-nitrophenyl)-2-(3’,4’,5’-trimethoxybenzoyl)quinoline（270）....................................……………..………………..…..….…157
6-Methoxy-5-(4’’-methoxyphenyl)- 2- (3’,4’,5’-trimethoxybenzoyl)- quinoline（271）……………………………..………………………158
5-(4’’-Cyanophenyl)-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)- quinoline（272）.................……………..……….…………..…....…159
6-Methoxy-5-nitroquinoline（323）…………………………………159
2-Chloro-6-methoxy-5-nitroquinoline（322）……………………….160
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxyphenoxy)quinoline（324）.161
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxyphenylamino)quinoline（325）
…………………………………………………………………………………………………….…..161
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxyphenylthio)quinoline（326）..
…………………………………………………………….…………..162
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxyphenylsulfonyl)quinoline
（327）……………………………………..………………………………………………..…..162
6-Methoxy-5-nitro-2-(3’,4’,5’-trimethoxyphenyl)quinoline（328）…163
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenoxy)quinoline（254）…..164
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenylamino)quinoline（255）……………………………………………………………..…..164
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenylthio)quinoline（256）
……………………………..………………………………...……..…165
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenylsulfonyl)quinoline（257）…………………………………………………………......….166
5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxyphenyl)quinoline（258）…
……………………………...……………………………..………..…166
5,6,7-Trimethoxyquinoline-2-carboxaldehyde（329）………..…..…167
2-(4’-Methoxybenzoyl)-5,6,7-trimethoxyquinoline（273）……..…..168
2-(3’-Fluoro-4’-methoxybenzoyl)-5,6,7-trimethoxyquinoline（274）….....168
2-(4’-Fluorobenzoyl)-5,6,7-trimethoxyquinoline（275）……..………169
2-Chloro-5,6,7-Trimethoxyquinoline（331）………….………..……170
2-(4’-Methoxyphenyl)-5,6,7-trimethoxyquinoline（279）………...…171
2-(3’-Fluoro-4’-Methoxyphenyl)-5,6,7-trimethoxyquinoline（280）..172
2-[4’-(N,N-Dimethylamino)phenyl] -5,6,7-trimethoxyquinoline（281）..
……………………………..………………………………………......172
6,7,8-Trimethoxy-4-methylquinoline（335）……………..….………173
6,7,8-Trimethoxyquinoline-4-carbaldehyde（333）……………….…174
4-(4’-Methoxybenzoyl)-6,7,8-trimethoxyquinoline（276）...………..174
4-(3’-Fluoro-4’-methoxybenzoyl)-6,7,8-trimethoxyquinoline（277）.175
4-[4’-(N,N-Dimethyl)benzoyl]-6,7,8-trimethoxyquinoline（278）….176
6-Quinoxalinecarboxaldehyde（320）……………………………….176
6-(3’,4’,5’-Trimethoxybenzoyl)quinoxaline（282）.........……………177
6-Methoxy-2-methylquinazoline（287）………………….………….177
6-Methoxyquinazoline-2-carbaldehyde（308）………………..…….178
6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinazoline（283）………178
5-[6-Methoxy-2-(3’,4’,5’-dimethoxybenzoyl)quinoline]disodium phosphate（336）…………..………………………………………....179

伍、參考文獻………………………………………………………………....181

附錄一、化合物之氫核磁共振光譜.................................................................197
附錄二、已發表期刊………………………………………………………….279











表目錄
表一 Combretastatin-4P的臨床試驗狀況………………………………….17
表二 2-,3-,4-,5-,6-,7-,8-(3’,4’,5’-Trimethoxybenzoyl)quinolines類化合物的
抗癌生物活性……………………………………………………………………………..….106
表三 6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinolines類化合物的抗癌
生物活性…………………………………………………………………………………………109
表四 5-Amino-6-methoxy-2-phenylquinolines類化合物的抗癌生物活性
………………………………………………………………………………………………………..112
表五 6-Aroylquinoxaline、2-aroylquinazoline、5,6,7-trimethoxyquinolines
與6,7,8-trimethoxyquinolines類化合物的抗癌生物活性………………114
表六 化合物240、244、247、249、252的抗微管聚合活性………………….…116














圖目錄
圖一、全球人口死因統計數字及發展趨勢預測（2002~2030年）………………….1
圖二、細胞週期圖…………………………………………………………..….11
圖三、有絲分裂……………………………………………………………..….12
圖四、微小管的構造…………………………………………………………...13
圖五、微小管與各類抗有絲分裂藥物的結合部位……………………….…..16
圖六、Combretastatin A-4 衍生物…………………………………………………………………18
圖七、Combretastatin A-1 衍生物…………………………………………………………………18
圖八、Combretastatin A-4四大類型化合物…………………………………….…………………..….19
圖九、單原子連結類化合物……………………………………………….……...…20
圖十、Rational by Cushman and coworkers…………………...……….……....21
圖十一、Phenstatin類化合物……………………………………………………..……….………...22
圖十二、Phenstatin衍生物……………………………………………………………………..….…..22
圖十三、2-Aminobenzophenones類化合物……………………………………………………24
圖十四、3-Aminobenzophenones類化合物…………………………………………..…..…..25
圖十五、鹵素取代的aminobenzophenones類化合物………………………………….….26
圖十六、以氧原子、氮原子和亞甲基連結類化合物……………………….…27
圖十七、雙原子連結類化合物………………………………………………...27
圖十八、非環狀連結類化合物…………………………………………….…..28
圖十九、非環狀連結其它類化合物…………………………………………...30
圖二十、含氟原子抗癌藥………………………………………………….….30
圖二十一、含氟原子之Combretastatins……………………………………....31
圖二十二、Dioxolane與dioxane衍生物…………………………………………………….….32
圖二十三、非芳香環連結類化合物……………………………………….….33
圖二十四、2,3-Diaryl-4/5-hydroxy-cyclopent-2-en-1-one衍生物………….….…..33
圖二十五、雜芳香環連結類化合物（a）…………………………………………………..……35
圖二十六、雜芳香環連結類化合物（b）……………………………………………………….36
圖二十七、Triazole連結類化合物…………………………………………………………………37
圖二十八、五或六騈環雜環連結類化合物…………………………………...39
圖二十九、參原子連結類化合物…………………………………………..….39
圖三十、1,3-位雜環連結類化合物……………………………………………42
圖三十一、Benzo[b]thiophene類化合物………………………………………………………..43
圖三十二、α,β-不飽合酮連結類化合物（a）………………………………………………….44
圖三十三、α,β-不飽合酮連結類化合物（b）…………………………………………………44
圖三十四、Chalcones、flavones連結類化合物……………………………………………..45
圖三十五、四原子連結類化合物……………………………………………...46
圖三十六、修飾A環之combretastatin類化合物（a）………………………………..…..47
圖三十七、修飾A環之combretastatin類化合物（b）…………………………………..…48
圖三十八、修飾B環之combretastatin類化合物（a）…………………………………….50
圖三十九、修飾B環之combretastatin類化合物（b）……..………………………………51
圖四十、修飾B環之combretastatin類化合物（c）………………………………………..53
圖四十一、修飾B環之combretastatin類化合物（d）……………………………………..55
圖四十二、Aroylnaphthalenes衍生物…………………………………………………………….56
圖四十三、修飾B環之combretastatin類化合物（e）……………………………………57
圖四十四、2-苯醯基吲哚衍生物……………………………………………………….……….…59
圖四十五、2-苯醯基-3-胺基吲哚衍生物…………………………………………………….…59
圖四十六、1-苯醯基吲哚與3-苯醯基吲哚衍生物………………………………………...61
圖四十七、3-苯醯基吲哚衍生物（a）………………………………………………………….61
圖四十八、1-苯醯基吲哚衍生物（a）…………………………………………………………….62
圖四十九、3-苯醯基吲哚衍生物（b）………………………………………………………….63
圖五十、1-苯醯基吲哚衍生物（b）………………………………………………………………..64
圖五十一、3-苯醯基吲哚代謝物…………………………………………………………..………65
圖五十二、苯硫基吲哚衍生物…………………………………………….…..66
圖五十三、苯醯基吲哚衍生物………………………………………………...67
圖五十四、不同連結之CA-4衍生物…………………………………………..69
圖五十五、Quinoline類衍生物………………………………………….……..70
圖五十六、Aroylquinoline類衍生物（a）…………………………………….71
圖五十七、Aroylquinoline類衍生物（b）………………………….…………..71
圖五十八、5-Amino-6-methoxyquinoline類衍生物……………..…………....72
圖五十九、Aroylquinoline類衍生物（c）……………………………………..73
圖六十、Aroylquinoline類衍生物（d）………………………………………..74
圖六十一、5,6,7-Trimethoxyquinoline類衍生物…………………..………..…74
圖六十二、Aroylquinoxaline與aroylquinazoline類衍生物（e）……………….75
圖六十三、Aroylquinoline類衍生物之合成設計……………………………..78
圖六十四、2-, 3-, 4-, 5-, 6-, 7-, 8-Aroylquinolines逆合成分析……………………….79
圖六十五、5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline逆合成分析…………………………………………………………………………………………..88
圖六十六、5-Hydroxy-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline逆合成分析………………………………………………………………………………………..90
圖六十七、6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinazoline逆合成分析…………………………………………………………….…….………………….………92
圖六十八、2-Aroylquinoline逆合成分析……………………….…………………………..….94
圖六十九、5-Amino-6-methoxyquinoline逆合成分析………………………………..…97
圖七十、2-Aroyl-5,6,7-trimethoxyquinoline逆合成分析………………….………...…99
圖七十一、2-Phenyl-5,6,7-trimethoxyquinoline逆合成分析………………………..101
圖七十二、4-Aroyl-6,7,8-trimethoxyquinoline逆合成分析…………………………103
圖七十三、2-,3-,4-,5-,6-,7-,8-(3’,4’,5’-Trimethoxybenzoyl)quinolines類化合
物…..…………….………………………………………………………106
圖七十四、6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinolines類化合物....109
圖七十五、5-Amino-6-methoxy-2-phenylquinolines類化合物……………....111
圖七十六、6-Aroylquinoxaline、2-aroylquinazoline、5,6,7-trimethoxyquinolines
與6,7,8-trimethoxyquinolines類化合物……………….…………...113
圖七十七、化合物252、CA-4與AVE-8063分子模擬（molecular modeling）
圖………………………………………………………………..….117
















流程目錄
流程一、5,6,7-三甲氧基喹哪啶之合成…………………………….……….…76
流程二、6,7,8-三甲氧基喹哪啶之合成……………………………...………..76
流程三、6-甲氧基-2-甲基喹唑啉之合成…………………………….…….….77
流程四、2-, 3-, 4-, 5-, 6-, 7-, 8-Aroylquinolines化合物之合成………………….…..80
流程五、2-Methoxy-6-(3’,4’,5’-trimethoxybenzoyl)quinoline化合物之合成....80
流程六、6-(3’,4’,5’-Trimethoxybenzoyl)-1-methylquinoline N-oxide與
6-(3’,4’,5’-trimethoxybenzoyl)-1-methylquinolinium iodide化合物之合成…………………………………………………………………………………………..…….81
流程七、5-Amino-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合物
之合成……………………………………………………………………………………..…….82
流程八、5-Chloro, 5-bromo, 5-iodo-6-methoxy-2-(3’,4’,5’-trimethoxy- benzoyl)quinoline化合物之合成……………………………………..…….83
流程九、6-Methoxy-5-pyridinyl-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合
物之合成………………………………………………………………………………..………84
流程十、5-(4’’-Hydroxyphenyl)-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)-
quinoline化合物之合成…………………………………………………………..…….84
流程十一、5-Cyano-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合
物之合成……………………………………………………………………………………85
流程十二、6-Methoxy-2-(3'',4'',5''-trimethoxybenzoyl)quinoline-5-carboxamide
化合物之合成……………………………………………………………………...……85
流程十三、5-(3’’-Hydroxy-3’’-methylbut-1’’-ynyl)-6-methoxy-2-(3’,4’,5’-
trimethoxybenzoyl)quinoline化合物之合成………………………..……86
流程十四、8-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合物之合
成…………………………………………………………………………………………….…87
流程十五、5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合物之合成……………………………………………………..…….89
流程十六、5-Ethynyl-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline化合物之合成………………………..……………………..…….……91
流程十七、6-Methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinazoline化合物之合成……………………………………………………………………………………………..…93
流程十八、2-Aroylquinoline化合物之合成…………………………………………..….…95
流程十九、6-(3’,4’,5’-Trimethoxybenzoyl)quinoxaline化合物之合成…........96
流程二十、5-Amino-6-methoxyquinoline化合物之合成……………………………....98
流程二十一、2-Aroyl-5,6,7-trimethoxyquinoline化合物之合成……………….….100
流程二十二、2-Phenyl-5,6,7-trimethoxyquinoline化合物之合成………….……..102
流程二十三、4-Aroyl-6,7,8-trimethoxyquinoline化合物之合成…………….104

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