組織蛋白酶S (Cathepsin S)屬於溶酶體半胱胺酸蛋白酶，在人體中主要的作用是降解第二型組織相容性複合體中的恆定鏈，幫助抗原呈現過程。最近研究指出，在某些癌症或具有侵襲及轉移的腫瘤細胞中，組織蛋白酶S會被過度表達並證實與腫瘤細胞之侵襲及轉移有密切的關係。為能開發治療癌症的新方法，本實驗室致力於合成α-酮醯胺化合物作為組織蛋白酶S抑制劑，用以對抗腫瘤細胞轉移；先前實驗室經藥物篩選後所得到的化合物RJW-58 ，能成功地抑制老鼠中腫瘤細胞的轉移，並提高老鼠的存活率。然而RJW-58卻因水溶性（97.9 μg/mL）及半衰期（4.6 hr）不佳而限制其發展性，本論文之主要工作即為解決上述兩個問題，藉由前導藥物RJW-58之結構為基礎，設計並合成含有羧酸、氮-甲基化基團及三氮唑環三種類型的抑制劑；在本論文所合成出的組織蛋白酶S抑制劑中，修飾羧酸的化合物89b將抑制常數保持在10 nM之內，並成功提升水溶性（256.7 μg/mL）及半衰期（6.8 hr）。

　　Cathepsin S (CTSS), a lysosomal cysteine protease, plays a major role in antigen presentation through degradation of invariant chain associated with the major histocompatibility class II complex (MHC II). Recent studies have demonstrated that CTSS is highly expressed in malignant cancer cells and shows a direct correlation with cancer cells invasion, migration, and metastasis. To achieve a new therapeutic approach for cancer treatment, our laboratory have developed a series of non-cytotoxic α-ketoamides as potent CTSS inhibitors. Through the CTSS inhibition activity screening, we found RJW-58 showed obvious inhibition of tumor cell progression and increase of the survival rate of cancer transferred mice. However, because of poor solubility (97.9 μg/mL) and short half-life (4.6 hr), the development of RJW-58 had been limit. In this thesis, the main work can be summarized as finding the solution to questions as mentioned above. We synthesized three kinds of derivatives based on the structure of RJW-58, including the compounds which contain a carboxylic group, N-methylated moiety, respectively. Among the inhibitors of Cathepsin S we synthesized, compound 89b which contained a carboxylic group maintain inhibition constant in 10nM and show better water solubility (256.7 μg/mL) and half-life (6.8 hr).

目錄
目錄………………………………………………………………………I
圖表及流程………………………………………………………………………V
縮寫表………………………………………………………………………XI
第一章、緒論………………………………………………………………………1
1.1 前言………………………………………………………………………1
1.2 惡性腫瘤細胞之轉移………………………………………………………………………1
1.3 以腫瘤轉移為標靶之藥物治療………………………………………………………………………3
1.3.1 抑制受體酪氨酸激酶………………………………………………………………………3
1.3.2 抗血管新生………………………………………………………………………4
1.3.3 抗附著分子………………………………………………………………………4
1.3.4 抗腫瘤轉移訊號………………………………………………………………………5
1.3.5 抑制尿激酶型血纖維蛋白溶解酶原活化因子…………………………………………………………………6
1.3.6 抑制水解蛋白酶………………………………………………………………………6
1.4組織蛋白酶………………………………………………………………………7
1.5 組織蛋白酶S………………………………………………………………………10
1.5.1 組織蛋白酶S結構………………………………………………………………………10
1.5.2 組織蛋白酶S之生理作用………………………………………………………………………11
1.5.3組織蛋白酶S與癌症之關聯 ………………………………………………………………………12
1.5.4組織蛋白酶S水解機制………………………………………………………………………13
1.6 組織蛋白酶S抑制劑………………………………………………………………………14
1.6.1 設計組織蛋白酶S抑制劑………………………………………………………………………14
1.6.2 抑制劑彈頭………………………………………………………………………20
1.6.2.1 不可逆型抑制劑………………………………………………………………………20
1.6.2.2 可逆型抑制劑………………………………………………………………………22
1.6.2.2.1氰基類………………………………………………………………………22
1.6.2.2.2 脂肪性酮類………………………………………………………………………24
1.6.2.2.3 α-酮雜環類………………………………………………………………………25
1.6.2.2.4 α-酮醯胺類………………………………………………………………………26
1.6.2.2.5 醛類抑制劑………………………………………………………………………26
1.6.2.2.6 β-內醯胺基團………………………………………………………………………27
1.6.3 非胜肽骨架抑制劑………………………………………………………………………28
1.6.3.1 吡唑骨架………………………………………………………………………28
1.6.3.2 嘧啶骨架………………………………………………………………………29
1.6.3.3 嘌呤骨架………………………………………………………………………30
1.6.3.4 三氮唑骨架………………………………………………………………………31
1.7 類肽學………………………………………………………………………31
1.7.1 生物電子等量取代………………………………………………………………………32
1.7.2 N-甲基化胜肽………………………………………………………………………32
1.7.3 類肽………………………………………………………………………33
1.7.4 β-胜肽………………………………………………………………………34
1.7.5 環化胜肽………………………………………………………………………34
1.8 重要合成反應介紹………………………………………………………………………36
1.8.1 Passerini 反應………………………………………………………………………36
1.8.2 點擊反應………………………………………………………………………37
1.9 組織蛋白酶 S抑制常數測試………………………………………………………………………38
第二章、研究動機與構想………………………………………………39
第三章、結果與討論……………………………………………………42
3.1 合成P3位置帶負電荷基團之α-酮醯胺胜肽抑制劑……………………………………………………42
3.2 探討P3位置修飾之結構與活性關係……………………………………………………49
3.3 合成非肽類抑制劑化合物……………………………………………………52
3.3.1 以三氮唑環取代醯胺鍵……………………………………………………52
3.3.2 以N-甲基化醯胺鍵取代醯胺鍵……………………………………………………60
3.3.3利用點擊反應修飾含水溶性之基團……………………………………………………68
3.4 水溶性量化……………………………………………………72
3.5 藥物動力學實驗結果討論……………………………………………………75
3.6 結論……………………………………………………77
第四章、實驗部分……………………………………………………80
4.1一般實驗方法……………………………………………………80
4.2組織蛋白酶S抑制活性測試……………………………………………………81
4.3實驗步驟及光譜資料……………………………………………………82
參考文獻………………………………………………………………121
附錄……………………………………………………………………132

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