本計畫為期三年，主要包含了三個同內容:(一）、合成新穎七圓環含硫分子（thiepanes)與具有 sulfate salt的側鏈，作為醣水解酵素之抑制劑（glycosidase inhibitors) ； (二）合成含氨基之黃酮類分子 (aminoflavones)，作為良好之抗氧化劑；（三）發展新合成OSW-1及其類似物方法，作為良好之抗癌 藥物。 (一）首先，發展醣水解酵素抑制劑可用來治療一些疾病，最著名的是用來治療糖尿病。傳統上 這類分子以五環及六環的azasugars為主，其他也有研究將醣類的氧或氮取代成硫原子，但凡是含硫 的五環六環分子皆非好的醣水解酵素抑制劑，然而若連接了 sulfonium salt形成所謂zwitter ion pair， 其抑制效果顯著提升。以往我們有合成七環含硫分子能力，也曾發表一篇文章，然而合成過程中會有 重排反應而生成六環分子，所以我們今年欲合成新的七環含硫分子，並與側鏈（可以是已知以及新設 計的分子）偶合後並測其抑制效果。七圓環分子在結構上具有可變性(flexibility)，我們的目的除了建 立七圓環分子與侧鏈分子結構上的鑑定，並進而瞭解這類分子是否可以提高抑制效果。 (二）另外，系上有同仁以斑馬魚測試市售黃酮類分子的抗氧化能力，而理論計算同仁利用QSAR 方式預測，黃酮類分子環上若有氨基(NH2)的存在，可有效提升氧化力，因此已預測一系列不同位置 上具-OH或-NH2的分子，並預測其抗氧化能力。而天然物含氨基的黃酮類分子不多，所以我們設計 新的含氨基黃酮類分子，並以簡單方式合成，藉以比對QSAR的結果。而這類分子也可用來作為抗 癌藥物，系上也有同仁用黃酮類分子測試一些癌細胞，所以這將會是很好的合作模式。 (三）天然物中分離出OSW-1及其類似物具有抗癌效果。該分子具有類固醇主體及侧鏈，我們 欲提出較簡短合成方式，因類固醇可由市售獲得且不貴，所以我們必須著重在側鏈的合成，以及與類 固醇的連接方法，全部合成步驟約七至八步。 This proposal is three-year term. It is contained three different parts: (1) Design and thesis of novel thiepanes which incorporated a sulfonium salts side chain that serve as potential glycosidase inhibitors. (2) Design and synthesis of novel aminoflavones for evaluation of their antioxidant ability. (3) Developing a new synthetic strategy of OSW-1 and analogues for anticancer drugs. (1) Glycosidase inhibitors can be used for treatment of various kinds of diseases. Among them, the most famous one is diabetes. The promising glycosidase inhibitors are azasugars, normally included five-or six- membered ring. The oxygen atom at anomeric center of sugars was sometimes replaced with sulfur atom. These kinds of sugars, no matter five-or six-membered ring, are not good or even weaker inhibitors of glycosidase. However, when these molecules were incorporated with sulfonium salts to form a so-called zwitter ion pair, the inhibition was significantly enhanced. We have published a paper regarding to the synthesis of thiepanes. During the course, the six-membered of thiosugars were inevitable formation. Therefore, we propose a new synthesis of novel thiepanes and incorporate them with sulfonium salt. Since the flexibility in structures of seven-membered rings, it is interesting for us to determine their structures by NMR experiments. It is also valuable to test their biological activities to compare with the five-membered thiosugars cases. (2) Flavones are wide-spread in vegetables and fruits and contain many biological activities. My colleague tested the antioxidant ability of flavones on zebrafish larvae. The QSAR method was also used to predict the structures which are contributed their activity. The results showed the amino groups in flavones will enhance the ROS ability. In order to prove the prediction, we design and synthesize a series of aminoflavones for evaluation. We can also use these molecules to test on cancer cells. (3) The molecules of OSW-1 and analogues possessed anticancer effects. Their structures contained a steroid along with a side chain moiety. We proposed a concise synthesis of these molecules. The frame work of steroid can be obtained from the commercial product. We also design the side chain synthesis. The assembly of steroid and side chain is crucial steps for our synthesis. The convergent synthesis of these molecules is about seven to eight steps.