- 學位論文
I.對組蛋白去乙醯酶第八型選擇性抑制劑TMUAS26294結構優勢化以作為抗癌藥物Ⅱ.合成以吲哚為基礎-吖啶作為抗登革病毒藥物
I.Structure optimization for HDAC 8 isoform-selective inhibitor TMUAS-26294 as anticancer agents Ⅱ.Synthesis and biological evaluation of indole-based acridines against dengue virus
摘要
本論文分為I.對組蛋白去乙醯酶第八型選擇性抑制劑TMUAS26294結構優勢化以作為抗癌藥物和II.合成以吲哚為基礎-吖啶作為抗登革病毒藥物 I.對組蛋白去乙醯酶第八型選擇性抑制劑TMUAS26294結構優勢化以作為抗癌藥物 在目前癌症標靶治療研究中，組蛋白去乙醯酶為一個重要的目標，因此其抑制劑為抗癌藥物之一種發展趨勢。組蛋白去乙醯酶抑制劑化學結構主要分為三部分：能與辨認組蛋白去乙醯酶產生結合的疏水性部位、能通過組蛋白去乙醯酶通道的疏水性鏈長及與鋅離子螯合之區塊。本研究主要以我們實驗室過去所發展組蛋白去乙醯酶第八型選擇性抑制劑(HDAC8i) TMUAS26294為先導化合物，進行結構修飾，以進一步提升其抗癌活性。 我們合成四個系列化合物：芳香環肉桂酸醯胺5a-5k，苯胺肉桂酸醯胺7a-7e以及在間位與對位分別具有三甲氧基苯胺之肉桂酸醯胺11和17。在第八型組蛋白去乙醯酶抑制活性中，均顯示比第八型組蛋白去乙醯酶抑制劑PCI34051有較強之活性；在抗癌活性方面，化合物5b、5e 和 5i對人類肺癌A549細胞，抑制活性與FDA核准之組蛋白去乙醯酶抑制劑SAHA效果相當，特別是5b (IC50<1 µM)對具高度轉移性且對臨床使用的多種抗癌藥有抗藥性的人類肺癌CL1-5細胞，抑制效果明顯優於SAHA (IC50=6.2 µM)，且在此濃度下對人類正常胚胎肺部纖維母細胞MRC5不具細胞毒性，因此證實化合物5b具有發展為有效抗癌藥物之潛力。 II.合成以吲哚為基礎-吖啶作為抗登革病毒藥物 登革熱為熱帶、亞熱帶須正視的一種疾病，高溫潮濕的氣候環境適合登革病毒病媒蚊生長，且感染人數有日益增加的趨勢，已成為世界性的公共衛生問題。但目前臨床缺乏預防的疫苗和治療用藥，處理方式以支持性療法治標。而根據文獻，吖啶(Acridine)有抑制病毒的效果，因此本實驗合成出吲哚為基礎-吖啶結構。 我們以吖啶為模板，合成吲哚啉20a-h和吲哚為基礎-吖啶21a-h共16個化合物，以感染登革病毒PL046株(dengue virus type 2 Taiwan local strain)之幼倉鼠腎臟纖維母細胞(BHK cells)為初步活性篩選平台。發現化合物 20c, 21b在2.5 µM分別即可抑制病毒活性達60%且對感染的細胞存活率均大於80%以上。由初步活性實驗結果得知病毒抑制率並非來自於細胞毒性，而是針對抑制病毒活性。
關鍵字
組蛋白去乙醯酶抑制劑；桂皮醯胺並列摘要
I.Structure optimization for HDAC8 isoform-selective inhibitor TMUAS-26294 as anticancer agents Histone deacetylase (HDAC) has been validated as a target in targeted therapy, thus its inhibitors become a trend for treatment of cancers. The pharmacophore of reported HDAC inhibitor is composed of three parts: a hydrophobic cap for surface recognition by HDAC enzymes, a connection group consisting of linear or cyclic linker to enter hydrophobic channel and a zinc-chelating group. In this study, we exploited a potent HDAC 8 isoform-selective inhibitor TMUAS26294 previously developed by our lab as a lead compound for structure optimization to improve the anticancer activity. We have synthesized four series compounds including ortho-aryl N-hydroxycinnamides 5a-k, ortho-anilinyl N-hydroxycinnamides 7a-e, meta-trimethoxyanilinyl N-hydrocycinnamide 11 and para-trimethoxyanilinyl N-hydroxycinnamide 17. Enzyme inhibitory activity test showed that all compounds exhibited anti-HDAC8 activity superior to HDAC8-specific inhibitor PCI34051. In addition, compounds 5b, 5e and 5i showed cytotoxicity against human lung cancer A549 cells compatible to SAHA, a pan HDAC inhibitor approved by FDA for treatment of cutaneous T-cell lymphoma (CTCL). Notably, compound 5b showed excellent antiproliferative activity (IC50<1 µM) against human lung cance CL1-5 cells with highly metastatic and drug-resistant potential comparable to that of SAHA (IC50=6.2 µM) but without significant cytotoxicity for human lung normal MRC5 cells. The results suggested that compound 5b has the potential to develop as an anticancer agent. II.Synthesis and biological evaluation of indole-based acridines against dengue virus Dengue fever is an infection disease in tropical and subtropical areas, which is caused by Dengue virus (DV). Nowadays, it became a tremendous threat for global public health. and it lacked for effective therapy such as vaccine and antiviral drugs for treatment of the disease. There is only supporting therapy to maintain proper fluid balance in clinic. Previous studies revealed that acridine had the inhibitory activity against virus. Thus, we have incorporated the drug-like indole into acridine to investigate the antivirus activity of resulting series. We have synthesized two series of acridines: with indoline 20a-h and with indole 21a-h and preliminarily screened resulting compounds for antivirus activity against PL046 strain (dengue virus type 2 Taiwan local strain) in baby hamster kidney (BHK) cells. It was noted that both compounds 20c and 21b, at 2.5 µM, can inhibit 60% virus growth without significant cytotoxicity for infected BHK cells.
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