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研究生:梁琡華
研究生(外文):Liang,Chu-Hua
論文名稱:具放療增敏與抗炎潛能之噻吩衍生物之合成
論文名稱(外文):Synthesis of Thiophene Derivatives as Potential Radiosensitizers and Antiinflammatory Agents
指導教授:李安榮,黃文鑫
指導教授(外文):An-Rong Lee,Wen-Hsin Huang
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:180
中文關鍵詞:放療增敏劑抗炎藥噻吩衍生物
外文關鍵詞:radiosensitizer agentsantiinflammatory agentsthiophene derivatives
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本實驗室依據先前合成benzothieno[2,3-c]quinolone化合物作為新型抗癌藥,經放療篩選,發現其benzothiophene之中間產物,具有強力增敏及保護放療作用。另外,文獻報導thiophene衍生物具抗炎活性,故本實驗室設計合成一系列benzothiophene及thiophene衍生物,以期開發高效低毒的新型放療增敏保護與抗炎藥。
分別以對甲氧基桂皮酸 (p-methoxycinnamic acid)、苯并噻吩-2-羧酸 (benzo[b]thiophene-2-carboxylic acid)、2-噻吩甲酸 (2-thiophenecarboxylic acid)、2-噻吩-3-烯酸 (3-(2-thienyl)acrylic acid)、2-噻吩乙酸 (2-thiopheneacetic acid)、2,5-噻吩二甲酸 (2,5-thiophenedicarboxylic acid)為起始物,加入過量亞磺醯氯 (thionyl chloride)於甲苯中迴流1-48小時而得到含醯氯之中間產物,未經純化下,即直接加入anilines反應而得到標的產物。
經初步活性試驗,合成之化合物中,皆具良好放療增敏效果,以T3c (48.2 %)最佳。另外,由MTS分析方法之結果顯示,化合物對於MCF-7、NCI-H460、SF-268三種癌細胞株在正常含氧條件之毒性試驗無明顯抗癌效果。而在鹿角菜誘導發炎動物模式進行抗炎藥物篩選中,化合物5c、5d、M3c、T3c抗炎活性較ibuprofen佳。
Our laboratory previously carried out the design and synthesis of a series of benzothieno[2,3-c]quinolone derivatives to develop novel anticancer drugs in our laboratories. After screening of the radiosensitizer/radioprotectant, the results showed that benzothiophene intermediates had strong potency to enhance the activity of radiation. On the other hand, literatures indicated that some thiophene derivatives possess significant antiinflammatory activity. Therefore, we further designed and synthesized a series of benzothiophene and thiophene derivatives to develop novel highly effective and low toxic radiosensitizers/radioprotectants and antiinflammatory drugs.
The starting materials, p-methoxycinnamic acid, benzo[b]thiophene-2-carboxylic acid, 2-thiophenecarboxylic acid, 3-(2-thienyl)acrylic acid, 2-thiopheneacetic acid, and 2,5-thiophenedicarboxylic acid, were respectively treated with excess thionyl chloride in toluene to the preparation of all the target compounds. After heating at reflux for 1-48 hours and being concentrated in vacuum, acyl intermediates without purification were further reacted with various anilines in the presence of triethylamine to afford the target compounds.
The preliminary results showed that benzothiophene and thiophene derivatives revealed potent radiosensization, especially T3c (48.2 %) superior to others. However, the results of target compounds by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay showed that none of the synthetic products were active against MCF-7 (breast carcinoma), NCI-H460 (lung cancer), or SF-268 (glioblastoma) cancer cell lines. On the other hand, compounds 5c、5d、M3c、T3c were much potent than ibuprofen after screening of the target compounds by carrageenan-induced paw edema model.
目錄
頁次
正文目錄………………………………………………………………..Ⅰ
附圖目錄………………………………………………………………..Ⅲ
中文摘要…………………………………………………………..……Ⅶ
英文摘要……………………………………………………………….Ⅷ

第一章、緒論………………………………………….………………….1
第一節、前言…………………………………….…………………..1
壹、癌症簡介………………………………..………………….1
貳、癌症治療藥物的方法……………..……………………….2
參、放射線……………………………..……………………….3
肆、放射線治療………………………..……………………….6
第二節、研究目的………………………….………………………..9
壹、放療增敏和保護劑………………..……………………….9
貳、研究目的…………………………….……………………18
第三節、研究方法…………………………….……………………22
壹、藥物設計原理.……………………….…………………...22
貳、合成反應概要……………………….……………………24
第二章、材料與方法……………………………………………………28
第一節、試藥來源…………………………………………………28
第二節、重要儀器…………………………………………………30
第三節、合成實驗…………………………………………………31
第四節、生物活性試驗……………………………………………44
壹、放療增敏/放療保護試驗…...……………………………44
貳、抗腫瘤活性試驗……………………….………………...45
參、抗炎活性試驗…………………………..………………..47
第三章、結果……………………………………………………………49
第一節、化學合成…………………………………………………49
第二節、生物活性…………………………………………………92
壹、放療增敏/放療保護試驗…...……………………………92貳、抗腫瘤活性試驗……………………….………………...94
參、抗炎活性試驗………………………………….………..96
第四章、討論…………………………………………………..………102
第一節、化學合成………………………………………..………102
第二節、生物活性………………………….…………………….124
第五章、結論…………………………………….……………….……129
第六章、參考文獻……………………………….…………………….130














表目錄
頁次
表一、Effect of 3a-3s and 3a*-3b* on the cell viability in Hela
cell……………………………………………………..………..19
表二、Antiinflammatory activity of 1-7….……………………….…..…20
表三、Effect of 4a – F7d on the cell viability in Hela cell…………...…92
表四、Effect of C3a – B8a on the cell viability in Hela cell…………....93
表五、Effect of T3a - D3d on the cell viability in Hela cell……….……93
表六、Effect of 4a – B8a on the cell viability in MCF-7, NCI-H460 and
SF-268…………………………………….………………….…94
表七、Effect of T3a - D3d on the cell viability in MCF-7, NCI-H460 and
SF-268…………………………………….………………….…95
表八、Antiinflammatory activity of 4a - 5d at dose 20 mg/kg i.p. for SD
rats…………………………………….……………...…………97
表九、Antiinflammatory activity of F7a - B8a at dose 20 mg/kg i.p. for
SD rats………………………….……………...…………….…98
表十、Antiinflammatory activity of T3a - M3d at dose 20 mg/kg i.p. for
SD rats………………………….……………...…………….…99
表十一、Antiinflammatory activity of D3a-D3d at dose 20 mg/kg i.p. for
SD rats……………………….………..……...…………….…100
表十二、Antiinflammatory activity of 5d、B8a、C3d、A3a、A3b、
M3c、M3d at dose 20 mg/kg i.p. for SD rats...………………..101
表十三、Antiinflammatory activity of
N-(Substituted-phenyl)-3-carboxamidyl-5-methylisoazoles at
dose 10 mg/kg i.p. for SD rats………………………………...117
表十四、Antiinflammatory activity of T3e - T3i at dose 20 mg/kg i.p. for
SD rats…………………………………………………….…..127
表十五、Antiinflammatory activity of T3e、T3f、T3h at dose 20 mg/kg
i.p. for SD rats………………………………………....….…..128



圖目錄
頁次圖一、癌細胞的形成…………………..…………………………………1
圖二、由鐳元素產生磁場而放出α、β與γ等射線…………………..3
圖三、直接及間接作用……………………….…………..……………...6
圖四、增敏及保護作用………………………….………………...……..9
圖五、鹵素嘧啶放射增敏劑結構………………………………....……11
圖六、缺氧細胞…………………………………………………………12
圖七、Hypoxic cell radiosensitizers的還原作用…………………….....13
圖八、Hypoxic cytotoxic agents的作用……………………..…….……14
圖九、Amifostine的去磷酸化作用……………………………..………16
圖十、Benzothieno[2,3-c]quinolone衍生物的合成………………….…18
圖十一、放療增敏/放療保護實驗步驟………………………..…….…44
圖十二、MTS與succinate dehydrogenase作用的結構變化圖………..45
圖十三、MTS分析方法實驗步驟…………………………...…………46
圖十四、Carrageenan誘發足蹠浮腫之事前給藥實驗步驟………..….48
圖十五、Structures of T3a and leflunomide analogs……………..……115
圖十六、化合物2之1H-NMR&13C圖譜………………..……………134
圖十七、化合物4a之1H-NMR&13C圖譜……………………..…..…135
圖十八、化合物4b之1H-NMR&13C圖譜…………..…………..……136
圖十九、化合物4c之1H-NMR&13C圖譜……………..…………...…137
圖二十、化合物4d之1H-NMR&13C圖譜………………..…………..138
圖二十一、化合物3之1H-NMR&13C圖譜………………………..…139
圖二十二、化合物5a之1H-NMR&13C圖譜…………………………140
圖二十三、化合物5b之1H-NMR&13C圖譜…………………………141
圖二十四、化合物5c之1H-NMR&13C圖譜………………..……...…142
圖二十五、化合物5d之1H-NMR&13C圖譜………..…….….………143
圖二十六、化合物F3之1H-NMR&13C圖譜…………………………144
圖二十七、化合物F4之1H-NMR&13C圖譜…………….………...…145
圖二十八、化合物F5之1H-NMR&13C圖譜……………….……...…146
圖二十九、化合物F7a之1H-NMR&13C圖譜……………………..…147
圖三十、化合物F7b之1H-NMR&13C圖譜…………………..………148
圖三十一、化合物F7c之1H-NMR&13C圖譜…………………..……149
圖三十二、化合物F7d之1H-NMR&13C圖譜……………..…………150
圖三十三、化合物C3a之1H-NMR&13C圖譜………..….……..……151
圖三十四、化合物C3b之1H-NMR&13C圖譜………………….……152
圖三十五、化合物C3c之1H-NMR&13C圖譜…………………..……153
圖三十六、化合物C3d之1H-NMR&13C圖譜………………….……154
圖三十七、化合物T3a之1H-NMR&13C圖譜……..…………………155
圖三十八、化合物T3b之1H-NMR&13C圖譜…………………….…156
圖三十九、化合物T3c之1H-NMR&13C圖譜……………………..…157
圖四十、化合物T3d之1H-NMR&13C圖譜………………….………158
圖四十一、化合物M3a之1H-NMR&13C圖譜………………….……159
圖四十二、化合物M3b之1H-NMR&13C圖譜………………………160
圖四十三、化合物M3c之1H-NMR&13C圖譜…………………….…161
圖四十四、化合物M3d之1H-NMR&13C圖譜………………………162
圖四十五、化合物A3a之1H-NMR&13C圖譜……………….………163
圖四十六、化合物A3b之1H-NMR&13C圖譜………………….……164
圖四十七、化合物A3c之1H-NMR&13C圖譜………………………..165
圖四十八、化合物A3d之1H-NMR&13C圖譜……………………….166
圖四十九、化合物D3a之1H-NMR&13C圖譜……………………….167
圖五十、化合物D3b之1H-NMR&13C圖譜………………………….168
圖五十一、化合物D3c之1H-NMR&13C圖譜…………………..……169
圖五十二、化合物D3d之1H-NMR&13C圖譜……………………….170
圖五十三、化合物B6a之1H-NMR&13C圖譜…………………..……171
圖五十四、化合物B7a之1H-NMR&13C圖譜………………………..172
圖五十五、化合物B8a之1H-NMR&13C圖譜………………………..173
圖五十六、化合物B9之1H-NMR&13C圖譜…………………………174
圖五十七、化合E2之1H-NMR&13C圖譜……………………………175
圖五十八、化合T3e之1H-NMR&13C圖譜…………………………..176
圖五十九、化合T3f之1H-NMR&13C圖譜…………………………..177
圖六十、化合T3g之1H-NMR&13C圖譜………………………….….178
圖六十一、化合T3h之1H-NMR&13C圖譜……………………….…179
圖六十二、化合T3i之1H-NMR&13C圖譜…………………………...180
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