我們設計並合成27個包含不同取代基(Cl, Br, OCH3, SCH3 or N(CH3)2)於芳香A環具烯雙炔結構之combretastatin A-4 (CA-4)衍生物，並評估化合物對於癌細胞的細胞毒活性(IC50)。其中，表現最優越抑制活性的化合物14a，對於Hep3B肝癌、A-549肺癌和MCF-7乳腺癌的IC50值分別為 0.22、0.49和0.22 μM，其活性比CA-4和引導化合物6好。此烯雙炔類似物14a可作為新的骨架而發展成為有潛力的抗腫瘤藥物。

A total of 27 new enediyne analogs of combretastatin A-4 (CA-4), with different substituents (Cl, Br, OCH3, SCH3 or N(CH3)2 ) of the aryl A-ring, were designed, synthesized, and evaluated for their growth inhibition activity against human tumor cell lines. Among them, compound 14a showed most significant inhibition activity against Hep3B (0.22 μM), A-549 (0.49 μM) and MCF-7 (0.22 μM), and these activities were greater than CA-4. The enediyne analog 14a may be consider as a new drug candidate worthy of further investigation and development as a potential antitumor agent.

摘 要........... i
Abstract...........ii
第一章 緒論 ...........1
1.1前言...........1
1.2 細胞週期 (Cell Cycle)...........2
1.3 抗有絲分裂抑制劑 (Antimitotic Agents)........... 5
1.4 Combretastatin A-4 (CA-4)...........9
1.5 新型烯雙炔 (Enediyne)...........11
1.6 CA-4衍生物...........20
第二章 合成具有烯雙炔結構之combretastatin A-4衍生物...........22
2.1 研究動機...........22
2.2 化學合成...........25
2.3 生物活性探討........... 33
2.4 結論...........41
第三章 化合物的製備方法...........42
3.1 儀器部分...........42
3.2 試藥部分...........43
3.3 實驗部分...........45
3.3.1方法A. 溴化反應...........45
3.3.2方法B. 還原反應...........46
3.3.3方法C. 碘化反應...........48
3.3.4方法D. 甲基化反應 (一)...........53
3.3.5方法E. 甲基化反應 (二)...........55
3.3.6方法F. Sonogashira偶合反應 (一)......................56
3.3.7方法G. Sonogashira偶合反應 (二)...........62
3.3.8方法H. 去矽反應...........64
3.3.9方法I. 去矽偶合反應...........67
第四章 參考文獻........... 96
光譜資料圖...........99

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