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研究生:薛莛婷
研究生(外文):Ting-Ting, Hsueh
論文名稱:合成新穎的Nilotinib 衍生物作為AMPK 促進劑
論文名稱(外文):Synthesis of novel Nilotinib analogues as AMPK agonists
指導教授:蕭崇瑋
指導教授(外文):Chung-Wai Shiau
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
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:41
中文關鍵詞:尼羅替尼AMP激活的蛋白激酶
外文關鍵詞:NilotinibAMPK
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AMP-activated kinase (AMPK) 是一種異源性三聚體蛋白質激酶,調控細胞內部的能量代謝,維持真核細胞ATP 生成和消耗的平衡。據研究指出,AMPK 在
調控細胞生長和增生中也有重要作用,當細胞內AMP/ATP 處於高比值狀態時,
會活化AMPK 導致細胞週期停滯,使生物合成及細胞生長受到抑制,因此對於
癌症的治療具有發展潛力。Nilotinib 為BCR-Abl 酪胺酸激酶抑制劑,FDA 核准用於治療慢性骨髓性白血病(CML)。先前我們的實驗結果發現nilotinib會抑制肝癌細胞生長,其主要原因是藉由刺激肝癌細胞中AMPK 的磷酸化而誘導細胞自
噬產生。因此我們實驗設計上是以nilotinib 當作引導化合物,合成一系列nilotinib結構類似物,作為AMPK 活化劑。我們利用三步驟合成反應進行化學修飾,成功合成出36 個nilotinib 衍生物,並探討結構與活性間關係,其中化合物SCT-1015對於提高AMPK 的磷酸化效果與抑制癌細胞生長效力與nilotinib 相同,顯示出化合物SCT-1015 作為AMPK 活化劑是具有發展性的。
5' AMP-activated protein kinase (AMPK) is a heterotrimeric complex which plays important roles in regulating energy homeostasis and maintaining the balance of ATP generation and consumption in eukaryotic cells. It is also a pivotal protein involved in cellular growth and proliferation. AMPK inhibits the biosynthesis of malignant tumor cells when it is activated by increasing the ratio of AMP:ATP to cause cell cycle arrest. Therefore it is a potential target for drug development.
Nilotinib, the second generation BCR-Abl tyrosine kinase inhibitor, which is approved by the FDA for the treatment of chronic myeloid leukemia (CML). Previous,our study revealed that nilotinib induced autophagy in hepatocellular carcinoma (HCC)through phosphorylating AMPK. In this study, we used nilotinib as a lead compound to develop a series of nilotinib derivatives as AMPK activators. Here, we synthesized 36 novel nilotinib analogues by 3-step procedures and studied the structure and activity relationship. Among then SCT-1015 showed similar effect to nilotinib in promoting p-AMPK level and cancer cells apoptosis. SCT-1015 may serve as promising lead compounds for further development of new AMPK activators.
誌謝 ........................................... i
中文摘要 ....................................... ii
英文摘要 ...................................... iii
目錄 .......................................... iv
圖目錄 ......................................... vi
第一章緒論 ...................................... 1
第一節 5' AMP-activated protein kinase 蛋白激酶功能 .................................... 1
第二節 AMPK 活化機制 ............................ 2
第三節 AMPK 調控功能............................. 3
第四節 AMPK 與癌症的關聯......................... 7
第五節 Nilotinib 酪胺酸激酶抑制劑................. 10
第二章研究目標及設計概念 .......................... 13
第三章實驗材料與方法 ............................. 15
第四章研究結果 .................................. 19
第一節 衍生物的合成方式........................... 19
第二節 A 環衍生物結構與活性分析 .....................22
第三節 B 環衍生物結構與活性分析 .................... 24
第四節 探討linker 為尿素結構衍生物之結構與活性分析 .... 24
第五節 新合成化合物對提升AMPK 訊息傳遞路徑活化的效果 ... 25
第六節 新合成化合物與BCR-Abl 激酶活性的關聯性 ........ 29
第七節 D 環衍生物結構與活性分析 ..................... 30
第五章 討論 ...................................... 32
第六章結論與未來工作 ............................... 37
參考文獻 ......................................... 38

圖目錄
圖一. AMPK組成及結構圖........................... 2
圖二. 活化AMPK模式 ................................3
圖三. AMPK調節功能 ................................6
圖四. AMPK調控細胞自噬機制..........................7
圖五. AMPK活化劑結構...............................10
圖六. Nilotinib 化學結構及nilotinib和Abl激酶間的相互作用..12
圖七. 兩種酪胺酸激酶抑制劑之結構、服用劑量、副作用及抗藥性 ...12
圖八. 設計理想化合物結構............................14
圖九. Nilotinib的逆合成...........................19
圖十. Nilotinib衍生物(SCT-1001~SCT-1012)合成步驟............20
圖十一. Nilotinib衍生物(SCT-1013~SCT-1041)合成步驟..........22
圖十二. 不同A環結構之化合物對PLC5肝癌細胞生長抑制效果............23
圖十三. 以尿素結構作為linker之不同A 環修飾化合物對PLC5 細胞生長抑制
效果..............................................25
圖十四. 新合成化合物促進AMPK磷酸化表現........................27
圖十五. SCT-1015衍生物、nilotinib與metformin對於PLC5肝癌細胞株之刺激AMPK磷酸化表現情形 ......28
圖十六. 新合成化合物在乳癌細胞株中刺激AMPK磷酸化表現.............29
圖十七. Nilotinib與SCT-1015抑制Abl激酶之活性表現.............30
圖十八. 化合物991結構之對照.................................31

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