臺灣博碩士論文加值系統

組織蛋白去乙醯酶抑制劑（Histone deacetylase inhibitor, HDACi）目前廣泛的用於治療癌症，其中已有多種藥物上市，例如默克藥廠的小分子化合物ZolinzaR（vorinostat, SAHA, FDA approved for treatment of refractory cutaneous T-call lymphoma in 2006）和Gloucester藥廠的RomidepsinR（FK-228, FDA approved for treatment of refractory cutaneous T-call lymphoma in 2009），以上都證明此類藥物為治療癌症之有效策略。
本實驗室觀察相關HDACi後發現，N-hydroxyacrylamide和benzamide等官能基在抑制活性上扮演重要角色；含氮之[6,5] 雜環，例如indole，在許多抗癌小分子化合物中為重要骨架，因此本實驗室決定探討含氮之[6,5] 雜環在其N位以苯磺胺類或是苯烷基連結，導入N-hydroxyacrylamide和benzamide官能基，合成二系列化合物，進一步了解HDAC抑制活性與結構之間關係。
實驗室合成出的二系列化合物對口腔上皮細胞癌KB cell line做生物活性試驗，目前已知的資料中12d、17d、24c、28b有相似的活性，其中以24c IC50 = 604.6 nM最好。目前其他化合物活性實驗仍在進行中，此後將會作HDAC抑制活性試驗與結構修飾。

Histone deacetylase inhibitors (HDACi) have been used for anticancer drugs broadly. Some of them were approved by FDA, for example ZolinzaR and RomidepsinR for treatment of refractory cutaneous T-call lymphoma. Therefore, to target histone deacetylase provides a potential methodology to develop potent anticancer agents.
To cording to the structures of HDACi, our laboratory found benzamide and N-hydroxyacrylamide important to HDAC inhibition activity. Besides, we observed some small molecular anticancer drugs containing nitrogen-containing [6,5]-fused heterocycles as major composition, for instance indole . So we introduced benzenesulfonamide or benzene motif on the N position of the nitrogen-containing [6,5]-fused heterocycles as the linker region and utilized N-hydroxyacrylamide and benzamide group for chelating region to discuss the relationship between structures and HDAC inhibition activity.
The two series of compounds are going to test KB cell line. According to the result, compound 12d, 17d, 24c and 28b have similar activity. Compound 24c possess the most potent inhibitory activity (IC50 = 604.6 nM). The evaluation of biological activities is still in progress. The further structural optimization and HDAC inhibition activity tests are going to be investigated.

附圖目錄 9
中文摘要 15
英文摘要 16
研究背景 17
實驗目的與設計 28
生物活性結果與討論 40
結論 41
實驗儀器 44
試藥與試劑 46
試藥與試劑簡寫表 49
合成步驟 50
indoline (1) 50
7-chloro-4-azaindole (2) 51
4-azaindole (3) 52
7-chloro-6-azaindole (4) 53
6-azaindole (5) 54
5-azaindole (6) 55
3-(chlorosulfonyl)benzoate (7) 56
methyl 3-(1H-indol-1-ylsulfonyl)benzoate (8a) 57
3-(1H-indol-1-ylsulfonyl)benzaldehyde (8b) 58
(E)-tert-butyl 3-(3-(1H-indol-1-ylsulfonyl)phenyl)acrylate (8c) 59
(E)-3-(3-(1H-indol-1-ylsulfonyl)phenyl)acrylic acid (8d) 60
(E)-3-(3-(1H-indol-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (8e) 61
methyl 3-(indolin-1-ylsulfonyl)benzoate (9a) 62
3-(indolin-1-ylsulfonyl)benzaldehyde (9b) 63
(E)-tert-butyl 3-(3-(indolin-1-ylsulfonyl)phenyl)acrylate (9c) 64
(E)-3-(3-(indolin-1-ylsulfonyl)phenyl)acrylic acid (9d) 65
(E)-N-hydroxy-3-(3-(indolin-1-ylsulfonyl)phenyl)acrylamide (9e) 66
1-(3-bromophenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (10a) 67
(E)-tert-butyl-3-(3-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)acrylate (10b) 68
(E)-3-(3-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (10c) 69
(E)-3-(3-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (10d) 70
1-(3-bromophenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (11a) 71
(E)-tert-butyl-3-(3-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylate (11b) 72
(E)-3-(3-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylic acid (11c) 73
(E)-3-(3-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (11d) 74
1-(3-bromophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (12a) 75
(E)-tert-butyl-3-(3-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylate (12b) 76
(E)-3-(3-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (12c) 77
(E)-3-(3-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (12d) 78
1-(3-bromophenylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (13a) 79
(E)-tert-butyl-3-(3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylate (13b) 80
(E)-3-(3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (13c) 81
(E)-3-(3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (13d) 82
1-(3-bromophenylsulfonyl)-1H-indazole (14a) 83
(E)-tert-butyl 3-(3-(1H-indazol-1-ylsulfonyl)phenyl)acrylate (14b) 84
(E)-3-(3-(1H-indazol-1-ylsulfonyl)phenyl)acrylic acid (14c) 85
(E)-3-(3-(1H-indazol-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (14d) 86
1-(4-bromophenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (15a) 87
(E)-tert-butyl-3-(4-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)acrylate (15b) 88
(E)-3-(4-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (15c) 89
(E)-3-(4-(1H-pyrrolo[3,2-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (15d) 90
1-(4-bromophenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (16a) 91
(E)-tert-butyl-3-(4-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylate (16b) 92
(E)-3-(4-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylic acid (16c) 93
(E)-3-(4-(1H-pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (16d) 94
1-(4-bromophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (17a) 95
(E)-tert-butyl-3-(4-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylate (17b) 96
(E)-3-(4-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (17c) 97
(E)-3-(4-(1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (17d) 98
1-(4-bromophenylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (18a) 99
(E)-tert-butyl-3-(4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylate (18b) 100
(E)-3-(4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)acrylic acid (18c) 101
(E)-3-(4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (18d) 102
1-(4-bromophenylsulfonyl)-1H-indazole (19a) 103
(E)-tert-butyl 3-(4-(1H-pyrazolo[3,4-b]pyridin-1-ylsulfonyl)phenyl) -acrylate (19b) 104
(E)-3-(4-(1H-indazol-1-ylsulfonyl)phenyl)acrylic acid (19c) 105
(E)-3-(4-(1H-indazol-1-ylsulfonyl)phenyl)-N-hydroxyacrylamide (19d) 106
4-(indolin-1-ylsulfonyl)benzoic acid (20a) 107
N-(2-aminophenyl)-4-(indolin-1-ylsulfonyl)benzamide (20b) 108
methyl 4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoate (21a) 109
4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzoic acid (21b) 110
4-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)-N-(2-aminophenyl)benzamide (21c) 111
methyl 4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzoate (22a) 112
4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)benzoic acid (22b) 113
4-((1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)-N-(2-aminophenyl)benzamide (22c) 114
methyl 4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)benzoate (23a) 115
4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)benzoic acid (23b) 116
4-((1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)-N-(2-aminophenyl)benzamide (23c) 117
methyl 4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzoate (24a) 118
4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzoic acid (24b) 119
4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-N-(2-aminophenyl)benzamide (24c) 120
methyl 4-((1H-indazol-1-yl)methyl)benzoate (25a) 121
4-((1H-indazol-1-yl)methyl)benzoic acid (25b) 122
4-((1H-indazol-1-yl)methyl)-N-(2-aminophenyl)benzamide (25c) 123
methyl 4-((1H-indol-1-yl)methyl)benzoate (26a) 124
4-((1H-indol-1-yl)methyl)benzoic acid (26b) 125
4-((1H-indol-1-yl)methyl)-N-(2-aminophenyl)benzamide (26c) 126
4-(indolin-1-ylmethyl)benzoic acid (27a) 127
N-(2-aminophenyl)-4-(indolin-1-ylmethyl)benzamide (27b) 128
4-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzoic acid (28a) 129
N-(2-aminophenyl)-4-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzamide (28b) 130
附圖部分 131
參考文獻 230

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