臺灣博碩士論文加值系統

以生物等效性的概念為基礎，先前已將N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzene- sulfonamide（ABT-751）此基本骨架進行修飾，合成出兩個新系列7-苯胺基-6-氮基吲哚-1-磺胺和7-苯基-6-氮基吲哚-1-磺胺且均具抗增生活性之化合物。ABT-751是透過和微小管上的秋水仙素鹼鍵結位置鍵結產生作用的口服有活性的抗癌化合物。現正在美國進行人體臨床試驗第二期。在先前的研究中發現 7-苯基-6-氮基吲哚-1-磺胺類衍生物的活性較7-苯胺基-6-氮基吲哚-1-磺胺類衍生物的活性強，於是更進一步研究其抗增生機轉與結構之間關係，另合成了7-苯基吲哚-1-磺胺和7-苯基二氫吲哚-1-磺胺。7-苯基吲哚-1-磺胺類衍生物是以1-溴基-2-硝基苯與乙烯基鎂溴反應後與4-甲氧基-磺基氯苯反應得到7-溴基吲哚-1-磺胺。七號位碳上溴基與各種苯硼酸進行鈴木偶合反應即可得到7-苯基吲哚-1-磺胺。7-苯基二氫吲哚-1-磺胺類衍生物是將1-溴基-2-硝基苯與乙烯基鎂溴反應後得到之7-溴基吲哚以氰基硼氫化鈉還原後與4-甲氧基-磺基氯苯反應得到7-溴基二氫吲哚-1-磺胺。七號位碳上溴基再與各種苯硼酸進行鈴木偶合反應得到7-苯基二氫吲哚-1-磺胺。化合物1, 2, 4, 5, 9, 11, 12, 14, 15, 23及24表現出強效抗癌活性，IC50 在15-50 nM之間。而其結構與活性的關係顯示7位碳上接有拉電子基之苯環或五員、六員雜環皆可增加其活性，但真正之機轉仍待進一步確立。

Two novel series of 7-anilino-6-azaindole-1-sulfonamides and 7-aryl-6- azaindole-1-sulfonamides based on N-[2-[(4-hydroxyphenyl) amino]-3- pyridinyl]-4-methoxybenzenesulfonamide (ABT-751) as a template were synthesized as potent antiproliferative agents. ABT-751 is an orally-active anticancer agent acting through the binding with the colchicine binding site on the tubulin. It is now undergoing human clinical trial. Based on the more potent antiproliferative activity of 7-aryl-6-azaindole-1-sulfonamides, another two novel series of 7- arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamides were synthesized. The synthesis of 7-aryl-6-azaindole-1-sulfonamide derivatives started from 2-bromo-3-nitropyridine, which was subjected to the vinyl magnesium bromide to give 7-bromo-6-azaindole, treated with 4-methoxybenzenesulfonyl chloride to afford the 6-azaindole -1-sulfonamides. A Suzuki reaction at 7-position, utilizing the 7-bromo -6-azaindole was treated with a variety of phenylboric acid to give the designed 7-aryl substituted 6-azaindoles. 7-arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamide derivatives were prepared started from 1-bromo-2- nitrobenzene by the same procedure. Three types of core structure analogous, for example, 7-aryl-6-azaindoles (20-24), 7-arylindoles (18-19) and 7-arylindolines (1-17) were evaluated their antiproliferative activity against oral epidermoid carcinoma KB cells. In the preliminary data, compounds 1, 2, 4, 5, 9, 11, 12, 14, 15, 23, and 24 demonstrate substantial activity with IC50 values ranging from 15-50 nM. Structure- activity relationship information revealed that 7-aryl-6- azaindole-1- sulfonamide and 7-arylindoline-1-sulfonamide derivatives were more potent than 7-arylindole-1-sulfonamide derivatives. These findings have encouraged us to extensively explore these two novel sulfonamides and further investigate their mode of actions and mechanisms.

目錄 1
附表目錄 5
附圖目錄 6
中文摘要 10
英文摘要 12
壹、緒論 14
一、前言 14
二、化學治療藥物3 17
三、微管與細胞增殖週期 29
四、作用在微管之抗癌藥物9 33
貳、研究背景 38
参、研究目的 44
肆、結果及討論 45
一、化學合成 45
二、生物活性（KB cell line） 55
三、結構與活性（Structure-Activity Relationship） 58
伍、結論 59
陸、實驗 60
一、實驗儀器 60
二、試藥與試劑 61
三、合成步驟 64
7-(3,4-Difluorophenyl)-1-(4-methoxyphenylsulfonyl)indoline (1) 64
7-(4-Hydroxyphenyl)-1-(4-methoxyphenylsulfonyl)indoline (2) 65
7-(4-Methoxyphenyl)-1-(4-methoxyphenylsulfonyl)indoline (3) 66
7-(4-Fluorophenyl)-1-(4-methoxyphenylsulfonyl)indoline (4) 67
7-(Furanyl-2-yl)-1-(4-methoxyphenylsulfonyl)indoline (5) 68
1-(4-Methoxyphenylsulfonyl)-7-(thiophen-2-yl)indoline (6) 69
7-(4-(N,N-dimethylamino)phenyl)-1-(4-methoxyphenylsulfonyl)indoline (7) 70
1-(4-Methoxyphenylsulfonyl)-7-(3,4,5-trimethoxyphenyl)indoline (8) 71
7-(4-Chlorophenyl)-1-(4-methoxyphenylsulfonyl)indoline (9) 72
1-(4-Methoxyphenylsulfonyl)-7-(4-(trifluoromethyl)phenyl)indoline (10) 73
7-(3-Fluorophenyl)-1-(4-methoxyphenylsulfonyl)indoline (11) 74
1-(4-Methoxyphenylsulfonyl)-7-phenylindoline (12) 75
1-(4-Methoxyphenylsulfonyl)-7-(3-pyridinyl)indoline (13) 76
1-(4-Methoxyphenylsulfonyl)-7-(4-nitrophenyl)indoline (14) 77
1-(4-Methoxyphenylsulfonyl)-7-(4-pyridinyl)indoline (15) 78
7-(4-Fluorophenyl)-1-(4-sulfonamidephenylsulfonyl)indoline (16) 79
7-(Pyridine-4-yl)-1-(4-sulfonamidephenylsulfonyl)indoline (17) 80
7-(4-Fluorophenyl)-1-(4- methoxyphenylsulfonyl)indole (18) 81
7-(4-Cyanophenyl)-1-(4- methoxyphenylsulfonyl)indole (19) 82
7-(4-Hydrophenyl)-1-(4-methoxyphenylsulfonyl)-6-azaindole (20) 83
1-(4-Methoxyphenylsulfonyl)-7-(4-pyridinyl)-6-azaindole (21) 84
1-(4-Methoxyphenylsulfonyl)-7-(4-nitrophenyl)-6-azaindole (22) 85
7-(2-Furanyl)-1-(4-methoxyphenylsulfonyl)-6-azaindole (23) 86
1-(4-Methoxyphenylsulfonyl)-7-(2-thiophenyl)-6-azaindole (24) 87
7-Bromo-1-(4-methoxyphenylsulfonyl)indoline (25) 88
7-Bromo-1-(4-sulfonamidephenylsulfonyl)indoline (26) 89
7-Bromo-1-(4-methoxyphenylsulfonyl)indole (27) 90
7-Bromo-1(4-methoxyphenylsulfonyl)-6-aza-indole (28) 91
7-Bromoindole (29) 92
7-Bromo-6-azaindole (30) 93
四、生物活性 94
柒、參考文獻 95
捌、附圖部分 100

附表目錄
表一、民國九十五年十大死因2 15
表二、化合物1-24抑制KB細胞株生長之活性 55

附圖目錄
圖一、民國九十五年臺灣地區主要死因死亡率趨勢圖2 16
圖二、細胞週期8 30
圖三、細胞週期 31
圖四、微小管的構造與動態性5 32
圖五、抗有絲分裂藥物於微小管的結合部位3 36
圖六、以苯磺醯胺（arylsulfonamide）為結構的藥物 39
圖七、ABT-751衍生化合物 43
圖八、化合物1的氫核磁共振圖 101
圖九、化合物1的碳核磁共振圖 102
圖十、化合物1的質譜圖 103
圖十一、化合物2的氫核磁共振圖 104
圖十二、化合物2的碳核磁共振圖 105
圖十三、化合物2的質譜圖 106
圖十四、化合物3的氫核磁共振圖 107
圖十五、化合物3的碳核磁共振圖 108
圖十六、化合物3的質譜圖 109
圖十七、化合物4的氫核磁共振圖 110
圖十八、化合物4的質譜圖 111
圖十九、化合物5的氫核磁共振圖 112
圖二十、化合物5的質譜圖 113
圖二十一、化合物6的氫核磁共振圖 114
圖二十二、化合物6的質譜圖 115
圖二十三、化合物7的氫核磁共振圖 116
圖二十四、化合物7的質譜圖 117
圖二十五、化合物8的氫核磁共振圖 118
圖二十六、化合物8的質譜圖 119
圖二十七、化合物9的氫核磁共振圖 120
圖二十八、化合物9的質譜圖 121
圖二十九、化合物10的氫核磁共振圖 122
圖三十、化合物10的質譜圖 123
圖三十一、化合物11的氫核磁共振圖 124
圖三十二、化合物11的質譜圖 125
圖三十三、化合物12的氫核磁共振圖 126
圖三十四、化合物12的質譜圖 127
圖三十五、化合物13的氫核磁共振圖 128
圖三十六、化合物13的質譜圖 129
圖三十七、化合物14的氫核磁共振圖 130
圖三十八、化合物14的質譜圖 131
圖三十九、化合物15的氫核磁共振圖 132
圖四十、化合物15的質譜圖 133
圖四十一、化合物16的氫核磁共振圖 134
圖四十二、化合物16的碳核磁共振圖 135
圖四十三、化合物16的質譜圖 136
圖四十四、化合物17的氫核磁共振圖 137
圖四十五、化合物17的質譜圖 138
圖四十六、化合物18的氫核磁共振圖 139
圖四十七、化合物18的碳核磁共振圖 140
圖四十八、化合物18的質譜圖 141
圖四十九、化合物19的質譜圖 142
圖五十、化合物20的氫核磁共振圖 143
圖五十一、化合物20的質譜圖 144
圖五十二、化合物21的氫核磁共振圖 145
圖五十三、化合物21的質譜圖 146
圖五十四、化合物22的氫核磁共振圖 147
圖五十五、化合物22的質譜圖 148
圖五十六、化合物23的氫核磁共振圖 149
圖五十七、化合物23的質譜圖 150
圖五十八、化合物24的氫核磁共振圖 151
圖五十九、化合物24的質譜圖 152
圖六十、化合物25的氫核磁共振圖 153
圖六十一、化合物26的氫核磁共振圖 154
圖六十二、化合物27的氫核磁共振圖 155
圖六十三、化合物4 的晶體結構圖 156
圖六十四、化合物15 的晶體結構圖 157

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