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研究生:吳家賢
研究生(外文):Chia-Hsien Wu
論文名稱:合成1-Aroylindoles/indolines為抗癌試劑
論文名稱(外文):Synthesis of 1-Aroylindoles/indolines as Anticancer Agents
指導教授:林美香林美香引用關係
指導教授(外文):Meihsiang Lin
口試委員:陳繼明李慶國胡明寬
口試日期:2014-01-10
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學系(碩博士班)
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:2014
畢業學年度:102
語文別:中文
論文頁數:367
中文關鍵詞:熱休克蛋白90
外文關鍵詞:Hsp90
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1960年代,Ritossa發現了“heat-shock”反應,並了解到chaperone的存在,也就是所謂的熱休克蛋白(Heat-shock proteins)。目前研究發現,癌症細胞中熱休克蛋白會異常地活化,以及維持癌細胞的生長。在熱休克異常活化的癌症中,發現Hsp90在腫瘤細胞中過度表現並且與黑色素瘤、乳腺癌、胃腸道基質腫瘤、非小細胞肺癌有密切的關聯。因此,Hsp90在抗癌發展中是一個重要的標靶藥物。

目前至少有二十個Hsp90抑制劑進入臨床試驗。目前進入臨床試驗的Hsp90 抑制劑有17-AAG (Tanespimycin),目前進入臨床三期,用於治療多發性骨髓瘤(Multiplemyeloma);BIIB021目前完成臨床二期,用於治療胃腸道基質瘤(Gastrointestinal Stromal Tumors)。

本實驗室參考了目前在臨床二期的Hsp90 inhibition AT13387,發現 2,4-dihydroxybenzamide是具有抑制活性的良好基團。因此,在結構設計上保留此基團,同時修飾isoindoline ring改變成1-aroylindole與1-aroylindoline,並在indole/indoline的4號位與5號位接上各種官能基,進而探討抑制活性與結構的相關性。由抗增殖活性數據顯示,發現在4號位接上-NH2的indoline ring化合物85具有較好的抗增殖活性,對於人類肺腺癌上皮A549細胞的GI50值為0.48 μM。
In the 1960s, Ritossa discovered the "heat-shock" response, and found the existence the chaperone which is also known as heat shock protein. Current study found that heat shock is overexpressed in cancer cells; In addition, it maintains the growth of cancer cells. Hsp90 is the most overexpressed among those heat shock proteins, and is highly associated with melanoma, breast cancer, gastrointestinal stromal tumors, and non-small cell lung cancer. Therefore, it becomes a significant target for developing anticancer agents.

Up to date there are more than 20 Hsp90 inhibitors undergoing the clinical trials. For example, 17-AAG (Tanespimycin) is currently undergoing phase III clinical trials, and is used in the treatment of multiple myeloma. BIIB021 is used to treat gastrointestinal stromal tumor, and has completed the phase II clinical trials.

AT13387, an Hsp90 inhibitor in the phase II clinical trial, was selected as the starting point of this thesis. Literature survey indicated that 2,4-dihydroxybenzamide group is an important moiety contributing biological activity. Hence, we retained the core, replaced the isoindoline ring with 1-aroylindole or 1-aroylindoline, and the substitution effects at C-4 and C-5 positions on biological activity is discussed as well with the expection to afford more active compounds. Compound 85 at with a C-4 -NH2 inhibited A549 cancer cell line with GI50 values of 0.48 μM.
標題 .............................................. i
審定書 ............................................ ii
電子暨紙本學位論文書目同意公開申請書 .............. iii
學位考試保密同意書暨簽到表 ........................ iv
誌謝 .............................................. vi
目錄 .............................................. vii
圖目錄 ............................................ xviii
表目錄 ............................................ xix
流程目錄 .......................................... xx
附錄目錄 .......................................... xxi
中文摘要 .......................................... xxviii
英文摘要 .......................................... xxix
論文相關化合物 .................................... xxx
第一章 緒論
1.1 前言 .......................................... 1
1.2 Molecular chaperone ........................... 3
1.3 Molecular chaperone 的生物活性 ................ 3
1.4 Heat shock protein 90 的結構與分類 ............ 4
1.4.1 N-terminal domain ............................................ 5
1.4.2 Highly charged linker ............................................ 5
1.4.3 Middle domain ............................... 5
1.4.4 C-terminal domain ........................... 5
1.5 Mechanism of Hsp90 in normal function .......................................... 6
1.5.1 Mechanism of Hsp90 inhibitor................. 6
1.6 Hsp90 在癌症上的應用 .......................... 7
1.7 Hsp90 抑制劑 .................................. 8
1.7.1 Geldanamycin 及其衍生物在臨床上的發展 ....... 8
1.7.2 Resorcinol 及其衍生物在臨床上的發展 ......... 9
第二章 Hsp90 抑制劑的實驗目的與設計
2.1 實驗設計構想 .................................. 11
第三章 Hsp90 抑制劑的化學合成
3.1 合成2,4-bis(benzyloxy)-5-isopropylbenzoic acid .............................................. 12
3.2 Aroylindoles/indolines 之合成 ................................................ 13
第四章 組蛋白去乙醯酶抑制劑的發展背景
4.1 前言 .......................................... 30
4.2 組蛋白去乙醯酶的生物活性 ...................... 30
4.2.1 組蛋白去乙醯酶的分類 ........................ 32
4.2.2 組蛋白去乙醯酶的位置及分佈 .................. 32
4.2.3 組蛋白去乙醯酶的生理功能 ........................................................... 33
4.3 組蛋白去乙醯酶之結構及其機轉研究 .............................................. 34
4.4 組蛋白去乙醯酶之藥理作用 .............................................................. 37
4.5 具有選擇性的組蛋白去乙醯酶抑制劑發展 ...................................... 40
4.6 HDAC-6 在癌症上的應用 .................................................................. 40
4.7 HDAC-6 抑制劑 .................................................................................. 41
4.7.1 HDAC-6 抑制劑在多發性骨髓瘤的發展 ....................................... 42
4.7.2 HDAC-6 抑制劑在乳腺癌與卵巢癌的發展 ................................... 43
4.7.3 HDAC-6 抑制劑在肺癌的發展 ....................................................... 43
4.7.4 HDAC-6 抑制劑在黑色素瘤、結腸癌與急性淋巴細胞白血病的
發展 .................................................................................................... 44
4.7.5 HDAC-6 抑制劑在自身免疫性疾病的發展 ................................... 45
4.7.6 HDAC-6 抑制劑在神經退化性疾病與氧化壓力下的發展 ........... 45
第五章 HDAC-6 抑制劑的實驗設計與合成
5.1 HDAC-6 抑制劑的實驗設計與合成 ....................... 46
第六章 結果與討論
6.1 抗癌活性試驗 ........................................ 52
第七章 實驗部分
7.1 實驗儀器及器材 ...................................... 59
7.2 化學試藥與試劑 ...................................... 60
7.3 實驗試藥與試劑簡寫表 ................................ 63
7.4 化學合成 ............................................ 64
第八章 參考資料 ........................................ 171
附錄 ................................................... 182
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