設計與合成以吲哚/喹啉類緣物作為抗癌藥物

組蛋白去乙醯酶 (histone deacetylase，HDAC) 的功能主要是藉由移除組蛋白以及非組蛋白之蛋白質上的乙醯基來調控多種細胞功能。多年來已有許多研究證實組蛋白去乙醯酶的過度表現對於癌症有著密切的關聯性，包含影響其細胞分化、增生以及細胞凋亡等，所以對於抗癌藥物的發展，是非常具有淺力的標靶。目前為止，組蛋白去乙醯酶抑制劑已廣泛單一使用或是與傳統化療藥物合併使近年來，有研究學者發現具有選擇性之組蛋白去乙醯酶6之抑制劑除了展現抗癌活性外，同時可下降心臟方面之副作用，故在本次研究中以設計蛋白去乙醯酶6之抑制劑為主，並分為兩部分討論。首先第一部分之設計原理，是根據目前市面與臨床試驗中 hydroxamic acids類的HDAC抑制劑，可以發現hydroxamic acid之官能基團會與HDAC之鋅離子的結合位產生鍵結，是抑制HDAC活性的主要機轉來源；另外根據市面上小分子抗癌藥物的發展與實驗室的經驗，含氮雜環時常作為藥物的中心結構。所以本論文將探討以吲哚及吲哚啉作為主架構，在N-1置入不同取代基，並嘗試在雜環之C-4至C-6上連接hydroxamic acids之官能基，以此合成一系列之化合物67-78，並且了解HDAC抑制劑之結構修飾與活性之間的相關性，結果顯示以化合物67之活性為最佳(HDAC 6 IC50 = 0.219μM)，但相較於對照組化合物7則明顯活性下降，雖然活性結果不如預期，但可針對本次修飾之發現做後續之探討及改善。另一部份，本論文則是對於實驗室已合成且擁有抗癌活性之化合物84進行修飾，嘗試改變其結構中之吲哚環，以此合成化合物85-87，並討論其中心結構的改變對於活性之影響性。由於此部分尚在進行中，期望能在未來完成這一部分的研究。

關鍵字

組蛋白去乙醯酶抑制劑；抗癌

並列摘要

Histone deacetylases (HDACs) are known to play a crucial role in the regulation of several cellular properties by removal of acetyl groups of histone and non-histone proteins. For many years, the evidences indicate that the over-expression of histone deacetylase (HDAC) has a close relationship with cancer, including impact on the cell differentiation, proliferation and apoptosis. Therefore, HDACs have been use in the clinical validation for cancer treatment. Recently, the scientists have discovered that selective HDAC6 inhibitors show an anticancer activity and are able to improve cardiac side effects. In this study, the discussion of the design of the HDAC6 inhibitors is separated into two parts. In the first part, the structure of the small molecular HDAC inhibitor in clinical or, preclinical trial indicated that the hydroxamic acid is active group and can interact with zincbinding site. Furthermore, the experiments have shown that when using nitrogen containing heterocycle structure as core structure, good activity can be obtained. In this study, indole and indoline were used as the core structures, and then different substitutes of N-1 position were introduced. Secondly, the heterocycles is linked to the symbolic hydroxamic acid group with various linkers in C-4 to C-6 position, which yielded a series of compounds, 67-78. The structure-activity relationship was also discussed in this study. The result showed compound 67 had the best activity (HDAC6 IC50 = 0.219 μM) amount the twelve compounds. However, the activity decreased significantly comparing to reference compound 7. Since the results were not as expected, further study can be done to improve the results. In the second part, this study utilized the compound 84 as main structure which was synthesis from our laboratory and shows anticancer activity. The study perform the modification of indole ring and synthesised a series of compounds 85-87. tried to discuss the impact in changing the core structure. Since this part of the study is still in process, a result is expected in the future.