由自然界靈感設計及合成出抗癌症和抗癌症轉移試劑：細胞和動物體內之活性測試評估

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傅志偉(Chih-Wei Fu) 查詢紙本館藏

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由自然界靈感設計及合成出抗癌症和抗癌症轉移試劑：細胞和動物體內之活性測試評估
(Nature-inspired anti-cancer and anti-metastatic agents: Design, synthesis and biological validation in vitro and in vivo)

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摘要(中)

主題一：以中心結構含有氮、雙氮及多氮雜環連接四個吲哚作為抗癌試劑之研究

我們實驗室於2012年在J. Med. Chem.發表過四吲哚衍生物SK228具有抑制乳癌增生能力，不過其溶解性差及在動物體中具有毒性高，於是此篇研究著重在改善其缺點。
在最佳化條件實驗中，我們發現利用I2/EtOH和CAN/ACN在迴流條件下分別可以催化2,5及2,6雙醛吡啶形成以吡啶為核心結構16種(化合物2-17)四吲哚衍生物，其中化合物14 (FCW81)是當中最具有抑制三陰性乳癌MDA-MB-231細胞株增生能力，其效果與SK228同屬奈莫爾濃度等級；此化合物可以誘導DNA斷裂、遏止細胞週期於G2/M和細胞凋亡；在移植乳癌細胞裸鼠實驗中可以有效抑制其腫瘤生長且其副作用大為降低，所以此化合物具有潛力成為抗三陰性乳癌試劑。
以多氮雜環為核心連接四吲哚衍生物已被合成出來，其中化合物24具有抑制乳癌MDA-MB-231及大腸癌SW480細胞株生長能力，其效果分別為0.37及1.08 μM，後續相關生物及動物實驗正在進行中。

主題二：合成石膽酸類似物含有不同長度疊氮長鏈做為唾液酸轉移酶抑制劑及抗癌症轉移試劑

近年來，癌症的轉移往往伴隨唾液酸轉移酶異常表現，本實驗室曾經開發出litho-O-Asp、AL10及KS034具有抑制此轉移酶能力，但其抗移轉效力的表現為適中。此研究著重在增加疊氮長鏈來增加其抗移轉能力並保有唾液酸轉移酶抑制效果及開發出具有選擇性唾液酸轉移酶抑制劑。
在第一代石膽酸衍生物中，我們合成出15種衍生物具有NBD、p-nitrobenzoyl或coumarin官能基之不同類型石膽酸衍生物含不同疊氮長鏈，發現化合物含有NBD結構石膽酸衍生物具有抑制唾液酸轉移酶能力效果與AL10及KS034相當，並且Ⅱ-2cA (FCW34)與Ⅱ-2dA (FCW66)二化合物在抗移轉能力是2或3倍優於AL10及KS034；在移植MDA-MB-231細胞的裸鼠移植瘤實驗中，FCW34試劑可以有效縮小腫瘤生長也同時抑制其癌症轉移，故化合物FCW34在抑制腫瘤生長及癌症轉移是有發展潛力。
在第二代石膽酸衍生物中，著重在石膽酸3號位置、胺基酸側鏈及芳香環上修飾，發現化合物FCW393及FCW551具有抑制唾液酸轉移酶能力效果與FCW34相當，並且在抗移轉能力是4倍或8倍優於FCW34，並且化合物FCW393在移植MDA-MB-231細胞的裸鼠移植瘤實驗中，可以有效縮小腫瘤生長也同時抑制其癌症轉移，故化合物FCW393在抑制腫瘤生長及癌症轉移亦具有發展潛力。

摘要(英)

Topic Ⅰ：Synthesis of core structure of one, two and many nitrogen atoms containing heterocycle with four indole derivatives as anti-cancer agents

Our previous developed tetraindole compounds, found that SK228 has a promising anti-cancer activity at the nanomolar range (J. Med. Chem. 2012, 55, 1583-1592). However, SK228 showed poor solubility and was toxic to the mice, our attempt is to improve these drawbacks in this study.
During optimization of reaction conditions, we synthesized a series of new tetraindole entities (compounds 2-17) containing a pyridine core at either 2, 5 position or 2, 6 position under I2/EtOH and CAN/ACN in reflux conditions, respectively. The results show that a potent candidate, 14 (FCW81) with a core structure of pyridine at 2,5 positions, has an optimum antiproliferative activity against human triple negative breast cancer (MDA-MB-231) cell, with similar anticancer potency compared to that of SK228. FCW81 induces DNA damage, G2/M arrest and apoptosis. Furthermore, FCW81 also significantly inhibited tumor growth in a xenograft human breast cancer mice model with apparent reduction of side effects. In summary, FCW81 has the potential to serve as an anticancer agent for the treatment of human breast cancers, especially in triple negative breast cancer.
A series of new tetraindole entities containing many nitrogen atoms heterocycle core was synthesized. Compound 24 had anticancer activity against triple negative breast cancer MDA-MB-231 and colon cancer SW480 cell lines with IC50 value 0.37 and 1.08 μM, respectively. The relative biological and animal studies are under progress.

Topic Ⅱ：Synthesis of lithocholic acid derivatives with different types of N3 linkers as sialyltransferase inhibitors and anti-metastatic agents

Recently, aberrant sialylation is found to be related to cancer metastasis. Our lab developed some sialyltransferase inhibitors, such as litho-O-Asp, AL10 and KS034, but they possessed moderate anti-migration inhibition in cellular level. This study focuses on developing the lithocholic acid derivatives to enhance the anti-migration activity with significant inhibition and selectivity of sialyltransferase.
The first generation of lithocholic acid derivatives was synthesized, 15 compounds (Ⅱ-2aA-2eA, Ⅱ-3aB-3eB and Ⅱ-4aC-4eC), containing the NBD, p-nitrobenzoyl or coumarin moieties with different length of azide linkers. We observed that lithocholic acid derivatives with NBD moiety have similar sialyltranferase inhibition in comparison to those of AL10 and KS034. Significantly, FCW34 and FCW66 had 2- or 3- folds anti-migration activity more than those of AL10 and KS034. Surprisingly, FCW34 meaningfully suppressed tumor growth and metastasis in a xenograft human breast cancer mice model. In summary, FCW34 had the potential to serve as an anti-metastasis agent for the treatment of human breast cancer with the unique inhibitory selectivity toward α(2,3)-N and α(2,6)-N sialyltransferases.
The second generation of lithocholic acid derivatives focuses on modification of lithocholic acid at C3 position, such as amino acid side chain and aromatic entities. The results showed that FCW393 and FCW551 had similar sialyltranferase inhibition in comparison to FCW34. Surprisingly, those FCW393 and FCW551 had 4- or 8- folds anti-migration activity more than that of FCW34. And FCW393 could effectively inhibited tumor growth and metastasis in a xenograft human breast cancer mice model. In summary, FCW393 display the potential to serve as an anti-metastasis agent for the treatment of human breast cancer with the unique inhibitory selectivity toward α(2,6)-N sialyltransferase.

關鍵字(中)

★ 吲哚
★ 癌症
★ 癌症轉移
★ 石膽酸
★ 唾液酸
★ 唾液酸轉移酶

關鍵字(英)

★ indole
★ cancer
★ cancer metastasis
★ lithocholic acid
★ sialyltransferase
★ sialyltransferase inhibitor

論文目次

目錄
摘要 i
Abstract iv
目錄 vi
圖目錄 viii
表目錄 x
流程目錄 xi
縮寫對照表 xii

主題一：以中心結構含有氮、雙氮及多氮雜環連接四個吲哚作為抗三陰性乳腺癌試劑之研究

1. 緒論 1
1-1 前言 1
1-2吲哚(indole)類衍生藥物 4
2. 結果與討論 7
2-1 實驗動機(pyridine系統) 7
2-2 化學部分(pyridine系統) 9
2-3 生物部分(pyridine系統) 22
2-4 實驗動機(雙氮及多氮雜環系統) 26
2-5 化學部分(雙氮及多氮雜環系統) 27
2-6 結論 33

主題二：合成石膽酸類似物含有不同長度疊氮長鏈做為唾液酸轉移酶抑制劑及抗癌症轉移試劑

3. 緒論 34
3-1 前言 34
3-2 癌症轉移與血管新生(angiogenesis)簡介 34
3-3 以癌症轉移過程為標靶之藥物治療 35
3-4 唾液酸與唾液酸轉移酶背景介紹 39
3-5 唾液酸轉移酶抑制劑 42
4. 結果與討論 48
4-1 實驗動機(不同長度疊氮長鏈系統) 48
4-2 化學部分(不同長度疊氮長鏈系統) 51
4-3 生物部分(不同長度疊氮長鏈系統) 56
4-4 實驗動機(酯鍵轉換成醯胺鍵系統) 59
4-5 化學部分(酯鍵轉換成醯胺鍵系統) 60
4-6 生物部分(酯鍵轉換成醯胺鍵系統) 68
4-7 實驗動機(改變胺基酸系統) 71
4-8 化學部分(改變胺基酸系統) 72
4-9 生物部分(改變胺基酸系統) 75
4-10 實驗動機(NBD結構上修飾系統) 76
4-11 化學部分(NBD結構上修飾系統) 77
4-12 生物部分(NBD結構上修飾系統) 80
4-13 實驗動機(石膽酸與C24上修飾系統) 81
4-14 實驗動機(石膽酸與C24上修飾系統) 82
4-15 結論 86
5. 實驗部分 88
5-1 一般實驗方法 88
5-2 主題一之化合物實驗步驟與光譜資料 92
5-3 主題二之化合物實驗步驟與光譜資料 110
6. 參考文獻 156
7. 附錄 170

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指導教授

李文山、侯敦仁(Wen-Shan Li Duen-Ren Hou)

審核日期

2015-12-7

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