合成芳醯基雜環及苄胺類衍生物作為抗癌試劑

根據2015 年衛生福利部公布之2014 年(民國103 年)國人死因統計結果可知，我國國人死因前三名為：(1)惡性腫瘤 (占28.9%)；(2)心臟疾病 (11.9%)；(3)腦血管疾病 (7.2%)。特別地是，惡性腫瘤從1982 年起已連續33 年高居國人死因首位，其占率遠高於排名第二之心臟疾病。由此數據可知癌症其嚴重性，而使產官學界主動地投入研究及發展去找尋新的療法。本論文希望以小分子標靶藥物為發展目標，文中研究目的與方法分為三部分：(1)[6,5]-及[6,-6]-雜環為主架構之衍生物；(2)苯甲醯苯胺衍生物；(3)8-(苯甲基氨基)喹啉衍生物。第一節以雜環為主架構之衍生物作為熱休克蛋白90 之抑制劑，許多抑制劑在臨床試驗階段，但未有美國食藥局核准之藥物，化合物18d 具良好的生物活性，A549 (GI50 = 0.73 μM)及HCT-116 (GI50 = 0.43 μM)。第二節源於近年來的研究顯示驅蟲劑耐克螺(niclosamide)具抗癌活性，故將耐克螺為研究對象，本節分兩部分探討一為以耐克螺之主結構苯甲醯苯胺為模板進行修飾，二為改善耐克螺之水溶性。第三部分以組蛋白去乙醯酶為標靶，根據過去本實驗室之成果MPT0G211 (47)，其生物活性PC-3 (IC50 = 3.40 μM)及A549 (IC50 = 5.24 μM)，但其酵素抑制活性分別為HDAC1 (IC50 = 6.70 μM)及HDAC6 (IC50 = 4.41*10-3 μM)，HDAC1/HDAC6 index = 1519，顯示其可能具HDAC6 之選擇性。為增加其抗癌活性，進一步進行修飾。

關鍵字

芳醯基雜環；苄胺；抗癌試劑

並列摘要

According to the 2014 statistical results on the causes of death in Taiwan published by the Ministry of Health and Welfare in 2015, three leading causes of death (COD) were: (1) malignant neoplasms (28.9% of all deaths); (2) heart disease (11.9%); (3) cerebrovascular disease (7.2%). Especially, malignant neoplasms have been the top of COD for 33 years in a row since 1982. The rate of death of malignant neoplasms is much higher than heart disease ranked second. We could know the seriousness of cancers from the statistical data, which prompts lots people from industries, government agencies and academic institutions to engage in research and development to find out new therapies. This thesis is aimed to the development of small molecule targeted drug and isdivided into three sections：(1) [6,5]- and [6,6]-heterocycles scaffold derivatives； (2) N-phenylbenzamides；(3) 8-(benzylamino)quinolines. The first section focuses on the development of heterocycle-based HSP90 inhibitors. Compound 18d exhibited marked activities against A549 (GI50 = 0.73 μM) and HCT-116 (GI50 = 0.43 μM). Literatural surveys indicated that niclosamide exhibited potent anticancer activity; therefore, the second section of this thesis worked on the modification of niclosamide. This section was divided into two parts; first part is based on the core of niclosamide,N-phenylbenzamide, as template to modify; second part is to improve the solubility of niclosamide. The target of the third section of this thesis is HDAC. Based on the result of our previous studies, MPT0G211 (47), it exhibited potent inhibitory activity against PC-3 (IC50 = 3.40 μM) and A549 (IC50 = 5.24 μM). The results of enzyme inhibition of HDAC1 (IC50 = 6.70 μM) and HDAC6 (IC50 = 4.41*10-3 μM). The selectivity ration of HDAC1 over HDAC6 is 1519, which indicated that synthetic compounds VII selectively inhibited HDAC6. To improve the anti-cancer activities, this thesis is planned to modify the synthetic compounds.