碩士 ; 國立清華大學 ; 化學系 ; GH000923424 ; 中文摘要 第一部分： 針對2003年在台灣造成重大影響的嚴重急性呼吸道症候群(SARS)，國家衛生研究院生物技術藥物研究組與台灣動物科技研究所、國防大學預防醫學研究所進行合作，共同研發抗SARS藥物。經過一個多月通力合作，由國家衛生研究院提供800個化學分子庫和化學修飾工作，台灣動物科技研究所提供第一階段豬的冠狀病毒篩選平台，以及預防醫學研究所提供第二階段SARS病毒篩選平台，已找出兩種不同類型之化合物，可有效抑制SARS病毒體外複製，並已向美國提出專利申請，本文針對抗精神病用藥Promazine為先導藥物，進行化學修飾工作，希望可以改善先導藥物之抗人類冠狀病毒的活性及各種藥理學上的性質，本文合成出一系列的Promazine衍生物，且應用了微波反應器，大幅減少反應時間，將原本需要數十小時的反應時間減短至數十分鐘。合成出的Promazine衍生物並送測其抗SARS病毒活性，期望能夠找到一高潛力候選藥物進入臨床實驗。 第二部份： Combretastatin是從南非的柳樹Combretum caffrum（African Willow tree）樹皮中分離出來的。Combretastatin A-4為Combretastatin系列中最有活性的化合物因為其擁有雙重特性既可抗微管聚合（細胞週期中G2-M）亦可抑制腫瘤血管增生，因此本實驗室針對Combretastatin A-4的結構，根據生物同位質理論設計出吲哚化合物29，並以多種細胞株進行抗癌活性測試，如對胃癌NUGC3、胃癌MKN45、子宮癌MESSA、肺癌A549、乳癌MCF-7等細胞株其IC50 ＝ 0.9-26 nM，比Combretastatin A-4的 IC50值低約50～100倍。雖然化合物29擁有良好的抗癌活性，但其水溶性與生體可用率不佳，故在此論文中以化合物29為標的化合物，進行構造修飾以期改善其水溶性與生體可用率。 ; Abstract The thesis consists of two parts: the first part is concerned with the synthesis and bioassay of promazine analogues and the second part describes the synthesis and anti-cancer activity of 3-phenoxy substituted indole analogues. The first part : The global outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus began in March 2003. An in-house chemical library consisting of 800 marketed drugs was evaluated for anti-SARS-CoV activities. We began our drug screening using porcine transmissible gastroenteritis virus (TGEV) as the surrogate system giving the similarities among several key viral proteins of TGEV and SARS-CoV. Hits that presented anti-TGEV activity then were subjected to the SARS-CoV assays. Several members of the phenothiazine drug class and niclosamide were found to inhibit SARS-CoV replication in cell culture at low concentration and thus both promazine and niclosamide were identified as the lead compounds for the structure optimization. For the lead optimization, we have synthesized 20 promazine analogues and subjected these to bioassay using TGEV and SARS –CoV for evaluating anti-viral activity. On the basis of these anti-viral assay, we have found compound 10 and 20 to exhibit good anti-SARS –CoV replication activities. During the synthesis of the promazine analogue, we tried to optimize conditions and found out that microwave technique has the advantage for it decreased reaction time and provided considerable yields of products. The second part : Compound 31, a potent anti-cancer drug synthesized by bioisosterism of Combretastatin A-4, was subjected to further modification through the replacement of sulfur bridge with oxygen. Two synthetic methods were employed for the target molecule. First, a C-O coupling strategies of Ullman and Buchwald-Hartwig were employed, but failed. We successfuly synthesized seven phenoxy indole analogues using the second strategy, Fisher Indole synthesis. The compounds were subjected to cytotoxic activity using KB and MKN45 cancer cell lines; compound 32d showed the highest activity with IC50 = 1.2 ± 0.5 nM for KB, and IC50 = 1.1 ± 0.1 nM for MKN45.