| 摘要: | I.利用微波反應合成以吲哚為基礎之吖啶作為抗阿茲海默症藥物
微波反應應用於藥物化學領域已為時數十年，相較於傳統加熱方式，利用微波反應進行化學合成能夠有效傳遞熱能、增加反應速率且改善產率。本篇研究中，我們優化微波輻射之反應條件，合成一系列以吲哚為基礎之吖啶3a-g，此系列化合物經由活性篩選發現能夠抑制乙型類澱粉蛋白之聚集，因此認為此系列化合物具有潛力作為抗阿茲海默症藥物。
II.開發氮-羥基醯胺類化合物以作為新型組蛋白去乙醯酶抑制劑
組蛋白去乙醯酶依照分布、結構和功能之不同可分為四類，其中有許多不同亞型蛋白存在，研究顯示選擇性抑制劑與廣泛性抑制劑相較下，具有效減少副作用的產生之潛力。延續實驗室過去所發展之能有效對抗癌細胞的化合物A5e做結構修飾，發展出對癌細胞有更佳抑制活性的藥物。我們合成一系列之羥基苯甲醯胺並在鄰、間和對位接上具有各種取代之苯胺，探討結構與活性之間關係。位於間位系列之化合物擁有針對HDAC6選擇性抑制活性，其中化合物11b取代基為3,4,5-trimethoxyaniline motif，在HeLa nuclear HDAC、HDAC6和HDAC4之活性測試當中，與抑制HeLa nuclear HDAC之活性相較下針對HDAC6選擇性效果達到19倍，由此活性數據結果推測，間位芳基之羥基苯甲醯胺針對HDAC6擁有不錯之抑制活性。
迄今為止，某些組蛋白去乙醯酶抑制劑已經在臨床上被美國FDA核准，但是在治療造血系惡性腫瘤時仍效果有限，因此，我們希望發展出一系列新的組蛋白去乙醯酶抑制劑能有效對抗固態腫瘤；SAHA依其化學結構分為三部分：與鋅離子螯合之基團、疏水性長碳鏈及辨識部位，我們將普遍使用於抗癌藥物中的磺醯基吲哚當作新的辨識部位，發展於磺醯基上帶有四個不同取代基之N-苯磺醯基吲哚20a-20d在HeLa nuclear HDAC酵素測試中均顯示比SAHA有更佳的活性，對HDAC6也與SAHA有相等之抑制活性，而化合物20a對於HeLa nuclear extract酵素與HDAC6顯示最佳的抑制活性。
I. Microwave-assisted Synthesis of Indole-based Acridines as Anti-Alzheimer Disease Agents
During last decade, microwave-activation has increasingly been used in pharmaceutical chemistry due to several advantages including improved yields, enhanced reaction rates and efficient energy compared to conventional heating approaches. In this study, we optimized the reaction condition for microwave irradiation to generate a novel series of acridines fused with various substituted indolines that act as a drug-like moiety. Through screening of the inhibitory activity of the resulting compounds against amyloid aggregation by thioflavin T binding assays, we identified that some of them exhibited strong activity and thus possibly had the potential to be developed as anti-Alzheimer disease agents.
II. Development of Novel N-Hydroxyamides as Histone Deacetylase Inhibitors
Based on their sequence homology, sub-cellular distribution and catalytic activity, histone deacetylase (HDAC) can be divided into four classes and these classes containeighteen isoforms. Isoform-selective HDAC inhibitors reportedly have less side effects than pan ones. This study continued our work on compound A5e for improving its cytotoxicity against cancer cells. Three ortho-, meta-, para- anilines substituted series of novel N-hydroxybenzamides were synthesized and assayed for the HDAC enzyme inhibitory activity. Of these compounds, meta-substituted series exhibited potent HDAC6 inhibition. In particular, compound 11b with 3, 4, 5-trimethoxyaniline motif displayed 19-fold selectivity for HDAC6 over HeLa nuclear HDAC and HDAC4. These data suggested that meta-aryl group for N-hydroxybenzamide contributes positively to HDAC6 inhibitory activity.
To date, certain HDAC inhibitors have been clinically approved by FDA; however, they are limited to treat hematopoietic malignancies. Thus, we attempt to develop HDAC inhibitors effectively inhibiting solid tumors. The pharmacophore of clinical HDAC inhibitor SAHA is composed of three parts: a zinc-binding group, a hydrophobic linker and a surface recognition cap. We used sulfonyl indole, which is a commonly used scaffold in anticancer agents, as a surface recognition cap and developed four indole-containing aliphatic hydroxamates 20a-20d with varied sulfonyl groups. Most compounds had higher inhibitory activity against HeLa nuclear HDAC than SAHA as well as anti-HDAC6 activity equivalent to SAHA. Notably, compound 20a exhibited the strongest activity for both HeLa nuclear HDAC and HDAC6. |
