合成胺基苄衍生物為抗癌試劑

組蛋白去乙醯酶(histone deacetylase; HDAC)與癌細胞的生長相關，除了癌症治療之外，也可作為其他疾病的治療標靶。目前已有兩個組蛋白去乙醯酶抑制劑 (HDACi) SAHA (ZolinzaR )與FK228 (IstodaxR )，分別在2006 和2009 年獲得美國 FDA 核准用於治療皮膚T 細胞淋巴瘤，除此之外，還有許多HDACi 正在臨床試驗中。研究發現hydroxamic acid 結構在癌症的治療領域上為活性的部分，此類抗癌藥物持續發展中。在表觀遺傳中，組蛋白的乙醯化和去乙醯化是由兩種酵素所調節：組蛋白乙醯轉移酶和組蛋白去乙醯酶。在細胞核內，組蛋白的乙醯化和去乙醯化過程是處於動態帄衡的狀態，因為染色質的重塑會因為組蛋白的乙醯化和去乙醯化而使構形不同，形成「開」與「關」之形狀產生，因此組蛋白在基因的表達上扮演重要的角色。現今對於組蛋白的研究著重在選擇性抑制劑的開發，特別是組蛋白去乙醯酶 6 (HDAC6)，HDAC6 在許多訊號傳遞的路徑上具重要性，亦被認為是癌症治療的標靶目標。本論文將tubastatin A 的結構特徵與雜環結合，設計與合成一系列胺基苄化合物，期望選擇性抑制HDAC6 同時具有良好的抗癌活性。近幾年雙效抑制劑的開發亦吸引許多研究學者的注意，透過兩個不同作用機轉的分子進行結構結合，期望達到增加活性及降低副作用的效果。研究指出 pargyline 能誘導癌細胞週期停滯在G1 期並促進癌細胞凋亡，因此，本論文將組蛋白去乙醯酶抑制劑與單胺氧化酶抑制劑相結合，設計與合成一系列含有 prop-2-ynylamine 之胺基苄化合物，期望能展現MAO/HDAC 雙重抑制效果，以增強抗癌的效果。

關鍵字

組蛋白去乙醯酶組蛋白去乙醯基酶6 ；單胺氧化酶組蛋白去甲基酶

並列摘要

英文摘要 Histone deacetylase plays an important role in the growth of cancer cells, and it is considered as therapeutic targets of several diseases in addition to cancer. To date, two HDACis, SAHA (Zolinza R ) and romodepsin (Istodax R ), have been approved for the treatment of cutaneous T-cell lymphoma by FDA in 2006 and 2009. Moreover, many HDACis have been developed and are undergoing clinical trials. Literature survey indicated that hydroxamic acid moiety contributes the biological activity and attracts numerous scientific attentions to this field. In the epigenetic process, histone acetylation and deacetylation are regulated by two enzymes: histone acetyltransferase and histone deacetylases. Histone acetylation and deacetylation process is in dynamic equilibrium state in the nucleus, and they lead to conformaitonal change of chromatin, which forms the conformations of “open ” and “close”. Therefore, histone plays a significance role in gene expression. Current study in HDAC is focused on the development of selective inhibitor, specifically histone deacetylase 6 (HDAC6). In addition to its siginicant influence in signaling pathway, it is recognized as a target for cancer treatment as well. This thesis is aimed to combine the structural feature of tubastatin A with heterocyclic derivatives. As a result, a series of aminobenzyl analogues is designed and synthesized as potent anticancer agents with selective HDAC6 inhibitory activity. Scientific attention is drawn to the development of compounds with dual functions and fewer side effects by combining symbolic structures from compounds with different mechanisms. Pargyline is reported inducing apoptosis through arresting the cell cycle in G1 phase. With a goal to develop dual HDAC/MAO inhibitors with potent anticancer activity, a series of prop-2-ynylamine-containing aminobenzyl analogues was synthesized by hybridizing the structural properties of HDAC and MAO inhibitors.