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系統識別號 U0007-2207201113385300
論文名稱(中文) 設計與合成具羥氨基吲哚類緣物為組蛋白去乙醯化酶抑制劑
論文名稱(英文) Design and Synthesis of Hydroxyamino-indole Analogues as Histone Deacetylase Inhibitors
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 李昱萱
研究生(英文) Yu-Hsuan Li
學號 M301098018
學位類別 碩士
語文別 中文
口試日期 2011-07-07
論文頁數 142頁
口試委員 委員-陳繼明
委員- 李慶國
指導教授-劉景平
中文關鍵字 組蛋白去乙醯化酶  抑制劑 
英文關鍵字 Histone Deacetylase Inhibitors 
學科別分類
中文摘要 本實驗室之前合成具有良好的抗癌活性的組蛋白去乙醯酶抑制劑-化合物11。本論文以化合物11為先導化合物,發展更有潛力的組蛋白去乙醯酶抑制劑,因此,在5-N-羥基丙烯酰胺基-1-磺酰二氫吲哚為骨架,在7號位導入不同的官能基團,進一步來探討結構與活性的關係。
在合成方法中,在二氫吲哚化合物的七號位,利用N-鹵基琥珀醯亞胺試劑導入鹵素原子。此外,經由鈀催化交叉耦合反應,例如:鈴木耦合、薗頭耦合反應,將許多不同的官能基團導入5-N-羥基丙烯酰胺基-1-磺酰-二氫吲哚化合物的七號位。最後,N-羥基丙烯酰胺基使用不同的條件的赫克反應將之導入。
結構與活性的關係結果顯示,大基團,例如:苯基或是吡嘧啶基,在體外測試具有中等的細胞毒性,因此,立體障礙在5-N-羥基丙烯酰胺基-1-磺酰二氫吲哚的七號位扮演的重要的角色,七號位為拉電子基具有相同的結果;在七號位導入氨基的12b具有強效的細胞毒性。根據結構與活性關係推斷,在5-N-羥基丙烯酰胺基-1-磺酰-二氫吲哚化合物的七號位導入立體障礙小且推電子基,可發展為具有潛力的組蛋白去乙醯酶抑制劑。
合成一系列的5-N-羥基丙烯酰胺基-1-磺酰-7-取代基二氫吲哚化合物,其在體外測試顯示具有明顯的細胞毒性,其中七號位導入氨基的吲哚12b,具有強效的細胞毒性,期望其比11有更好得物化性質。因此,生物活性的結果激勵我們更進一步研究並設計合成7-氨基-5-N-羥基丙烯酰胺基-1-磺酰-二氫吲哚衍生物,期望得到更有抗癌潛力的組蛋白去乙醯酶抑制劑。
英文摘要 In our laboratory, 11 was identified as histone deacetylase (HDAC) inhibitor and demonstrated excellent anticancer activity in vitro. In this master thesis, 11 was chosen as lead compound to develop more potential inhibitors. Therefore, a variety of functional group was introduced into at the C-7 position of 5-(N-hydroxyacryamide)-1-sulfonyl indoline to investigate further structure-activity relationship (SAR).
In the synthetic strategy, the halogen atom at C-7 position of 5-(N-hydroxyacryamide)-1-sulfonyl indoline was made by N-halosuccinimide reagents. Moreover, a lot of different function group were introduced into the C-7 position of indoline via palladium-catalyzed cross coupling reaction, such as Suzuki and Sonogashira coupling reaction. Finally, the N-hydroxyacrylamide group at C-5 position of indoline was collected by Heck reaction with different conditions.
The SAR result of these compounds have been analyzed that bulky group, such as phenyl or pyridyl group revealed moderate cytotoxicity in vitro. Hence, steric hinderance plays an important role at C-7 position of indoline. Moreover, electron-withdrawing groups exhibit the same result at C-7 position of indole. However, 12b inserting amino group at C-7 position of indole displays potent cytotoxicity in vitro. On the basis of SAR analysis, the C-7 position of 5- (N-hydroxyacryamide)-1-sulfonyl indoline result in a characteristic features with small steric hinderance and electron-donating groups favor potential HDAC inhibitors.
A series of 5-(N-hydroxyacryamide)-1-sulfonyl-7-substitude indoline have been synthesized and showed obvious cytotoxicity in vitro. Within those compounds, 12b with amino group at C-7 position of indoline showed potent cytotoxicity. Expectedly, 12b would provide better physicochemical properties compared with 11. Therefore, the result inspires us to further investigation and design of 7-amino-5-(N-hydroxyacryamide)-sulfonyl indoline derivates and do further investigation to obtain more potential HDAC inhibitors as anticancer agents.
論文目次 目 錄
目 錄 I
表目錄 V
圖目錄 VI
流程圖目錄 IX
中文摘要 X
Abstract XI
縮寫對照表 XII
壹、緒論 1
1.1 前言 1
1.2 染色質重組 (chromatin remodeling) 2
1.3 組蛋白去乙醯酶(HDACs) 3
1.3.1 HDACs分類2,8 3
1.3.2 HDACs對非組蛋白的去乙醯化作用9,10 3
1.3.3 HDACs與癌症 3
1.4 組蛋白去乙醯酶抑制劑(Histone deacetylase inhibitor, HDACi)與作用 4
貳、研究構想 8
2.1 藥物設計理念 8
2.2 合成策略 9
參、結果與討論 11
3.1 化學合成 11
3.2 化學結構與抗癌活性關係之探討 28
3.2.1 抗癌細胞活性試驗結果 28
3.2.2化學結構與抗癌活性關係 29
肆、結論 31
伍、實驗部份 32
5.1實驗試劑與儀器 32
5.2合成步驟 35
5-Bromo-1-(4-methoxyphenylsulfonyl)-7-nitroindoline (14)18 35
(E)-Methyl 3-(1-(4-methoxyphenylsulfonyl)-7-nitroindolin-5-yl)acrylate (15) 36
(E)-3-(1-(4-Methoxyphenylsulfonyl)-7-nitroindolin-5-yl)acrylic acid (16) 37
(E)-N-Hydroxy-3-(1-(4-methoxyphenylsulfonyl)-7-nitroindolin-5-yl)acrylamide (12a) 38
(E)-Methyl 3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (17) 39
(E)-3-(7-Amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylic acid (18) 40
(E)-3-(7-Amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12b) 41
7-Benzyloxyindoline (22)31 42
7-Benzyloxy-5-bromoindoline (23) 43
7-Benzyloxy-5-bromo-1-(4-methoxyphenylsulfonyl)indoline (24) 44
(E)-Methyl 3-(7-(benzyloxy)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (25) 45
(E)-3-(7-(Benzyloxy)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylic acid (26) 46
(E)-3-(7-(Benzyloxy)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12c) 47
Methyl indoline-5-carboxylate (28)32 48
Methyl 7-bromoindoline-5-carboxylate (29) 49
Methyl 7-bromo-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylate (30) 50
7-Bromo-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylic acid (31) 51
(7-Bromo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)methanol (32) 52
7-Bromo-1-(4-methoxyphenylsulfonyl)indoline-5-carbaldehyde (33) 53
(E)-Methyl 3-(7-bromo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (34) 54
(E)-3-(7-Bromo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylic acid (35) 55
(E)-3-(7-Bromo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12d) 56
Methyl 7-chloroindoline-5-carboxylate (36) 57
Methyl 7-chloro-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylate (37) 58
7-Chloro-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylic acid (38) 59
(7-Chloro-1-(4-methoxyphenylsulfonyl)indolin-5-yl)methanol (39) 60
7-Chloro-1-(4-methoxyphenylsulfonyl)indoline-5-carbaldehyde (40) 61
(E)-Methyl 3-(7-chloro-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (41) 62
(E)-3-(7-Chloro-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12e) 63
Methyl 7-iodoindoline-5-carboxylate (43) 64
Methyl 7-iodo-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylate (44) 65
7-Iodo-1-(4-methoxyphenylsulfonyl)indoline-5-carboxylic acid (45) 66
(7-Iodo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)methanol (46) 67
7-Iodo-1-(4-methoxyphenylsulfonyl)indoline-5-carbaldehyde (47) 68
(E)-Methyl 3-(7-iodo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (48) 69
(E)-3-(7-Iodo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylic acid (49) 70
(E)-N-Hydroxy-3-(7-iodo-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylamide (12f) 71
(E)-Methyl 3-(7-cyano-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylate (51) 72
(E)-3-(7-Cyano-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12g) 73
(E)-Methyl-3-(7-(3-hydroxy-3-methylbut-1-ynyl)-1-(4-methoxyphenylsulfonyl) indolin-5-yl)acrylate (53) 74
(E)-3-(7-(3-Hydroxy-3-methylbut-1-ynyl)-1-(4-methoxyphenylsulfonyl)indolin-5- yl)acrylic acid (54) 75
(E)-N-Hydroxy-3-(7-(3-hydroxy-3-methylbut-1-ynyl)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylamide (12h) 76
(E)-3-(1-(4-Methoxyphenylsulfonyl)-7-phenylindolin-5-yl)acrylic acid (55) 77
(E)-N-Hydroxy-3-(1-(4-methoxyphenylsulfonyl)-7-phenylindolin-5-yl)acrylamide (12i) 78
(E)-3-(1-(4-Methoxyphenylsulfonyl)-7-(pyridin-4-yl)indolin-5-yl)acrylic acid (56) 79
(E)-N-Hydroxy-3-(1-(4-methoxyphenylsulfonyl)-7-(pyridin-4-yl)indolin-5-yl)acrylamide (12j) 80
(E)-3-(7-(4-Fluorophenyl)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)acrylic acid (57) 81
(E)-3-(7-(4-Fluorophenyl)-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide (12k) 82
陸、參考文獻 83
柒、附錄 86

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