由於突變、基因的過度表現，導致後生酶(Epigenetic enzymes)的失調、不正
常的作用，導致腫瘤的產生。組蛋白去乙醯酶(HDACs)，就是其中一種目前已知
的後生酶，其在基因的表現中扮演重要的調節者。HDACs 的作用為從組蛋白上
將乙醯基團移除，使得帶負電的DNA 會與帶正電的組蛋白纏繞的更緊密，使得
基因不被表現。然而，根據文獻指出，於癌細胞抑制HDACs 的活性，可以增加
組蛋白之乙醯化，與抗增殖作用有關，具有抗癌活性，除此之外，後來的研究
發現，其抗癌活性也與非組蛋白之乙醯化有關係。因此，近年來開發一系列的
HDAC 抑制劑，阻斷不正常的去乙醯化作用。根據文獻指出，發現hyroxamic acid之官能基團可與HDACs 之鋅離子鍵結位置產生鍵結，抑制HDACs 的活性。
ABT-751 是一種新穎的微管蛋白結合劑(tubulin-binding agent)和抗有絲分裂劑(antimitotic agent)。ABT-751 鍵結在s-tubulin 的colchicine site，抑制微管的聚合，其阻斷細胞週期之G2/M phase，藉而抑制有絲分裂的進行，具有開發成抗癌藥物的潛力。根據實驗室先前經驗發現ABT-751 之
4-methoxybenzenesulfonamides 在抗癌活性為重要的結構，因此，我們想要保留ABT-751 的4-methoxybenzenesulfonamides 結構，且將其極性基團之hydroxyl group 改為hyroxamic acid，期許有更好的抗癌活性。最後，我們可以從初步的活性數據看出，化合物22b 具有良好的選擇性抑制HDAC6 活性，且對於抑制癌細胞也有不錯的活性，期許更完整的活性數據，可以繼續探討結構與活性的關係，以作更進一步的延伸合成。

Epigenetic enzymes are often dysregulated in tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of
small-molecule inhibitors that target the cancer epigenome. Acetylation is generally associated with elevated transcription while deacetylated histones are often associated with gene repression. Histone deacetylases (HDACs) are critical regulators of gene expression that enzymatically remove the acetyl group from histones.
ABT-751 was shown to reversibly bind to the colchicine site of β-tubulin, thereby halting mitosis. Furthermore, the structure of ABT-751 inserting with hydroxamic acid, recently study indicated the hydroxamic acid can interact with zinc2+ binding site of HDAC catalytic pocket, was modified into a novel class of HDAC inhibitors.
Finally pharmacological data shows 22b has selective HDAC6 enzymatic activity and 41b has good antitumor activity.

目錄
目錄...................................................... I
圖目錄................................................... III
表目錄 ................................................... IV
流程目錄 ................................................. IV
附圖目錄 .................................................. V
中文摘要 ............................................... VIII
Abstract ................................................ IX
壹、前言 ...................................................1
1.1 背景介紹 ...............................................1
1.2 表觀遺傳學 (epigenetics)................................3
1.3 組蛋白 (histone) .......................................5
1.4 組蛋白之乙醯化和去乙醯化 ...........................................................6
1.5 組蛋白去乙醯酶之種類以及分布 ...............................7
1.6 HDAC 與癌症的關係 ......................................10
1.7 目前臨床發展中之HDAC 抑制劑...............................12
1.7.1 Vorinostat .........................................15
1.7.2 Depsipeptide .......................................16
1.7.3 Belinostat .........................................17
II
貳、實驗目的與設計 ..........................................18
2.1 化合物之構想與設計.......................................18
2.2 化合物之結構活性關係探討 .................................22
參、化合物合成 .............................................24
肆、實驗部分 ...............................................34
4.1 實驗儀器和檢驗方法.......................................34
4.2 實驗藥品和溶劑 .........................................34
4.3 試劑之縮寫 ............................................35
4.4 生物活性試驗與步驟.......................................36
伍、化合物合成步驟 ..........................................38
陸、結果與討論 .............................................66
6.1 化學合成 ..............................................66
6.2 藥理活性 ..............................................67
柒.參考文獻................................................72
附錄 .....................................................78

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