新近發展的組合式固相合成法能快速且同時合成多種具不同取代基之同一類型化合物，因此，已逐漸取代逐一合成單一衍生物的傳統方法，而成為開發藥物、催化劑、新材料等的重要利器。本研究計劃的主要研究重點在於探討固相組合式合成的新技巧及應用此技巧於藥物如protein tyrosine phosphatase 抑制劑及發光二極體 (organic light-emitting diodes, OLEDs) 所需之發光材料的開發。特定目標如下： A. 設計及合成具選擇性高活性的protein tyrosine phosphatase 抑制劑： 1. 鑑定PTP 抑制劑可與特殊受納體的鍵結部位與活性部位緊密錯合或鍵結的結構特性並經由結構-功能分析產生具高活性之抑制劑。 2. 探討組合式固相合成法以製備多種具不同取代基之protein tyrosine phosphatase 抑制劑。 3. 設計及製造新類型之低分子量的protein tyrosine phosphatase 抑制劑以便標地(target)特定受納體。 B. 生物活性評估protein tyrosine phosphatase 抑制劑： 1. 評估抑制劑的抑制性以便瞭解其生物特性與不同受納體間的相互關係作為設計及改良具高活性及選擇性抑制劑的依據。 2. 探討具選擇性的抑制劑與特定受納體的結構-生物活性之相關性 (SAR)。 3. 根據組合式合成、分子模擬及定量結構與活性關係 (QSAR) 分析，發展出具互補作用的rational combinatorial drug design 新概念並依此法研製新一代的 protein tyrosine phosphatase 抑制劑。 C. 開發新類型磷光發光材料： 1. 利用組合式技巧快速檢測、研製發光二極體 (organic light-emitting diodes, OLEDs) 所需之發光材料。 2. 探討發光材料之光電性質。 The goal of rapid discovery and optimization of pharmaceutical lead compounds has inspired intensive efforts toward the combinatorial synthesis of libraries of highly diverse molecules. The key feature of combinatorial chemistry is that the synthesis be designed to produce a range of analogs under similar reaction conditions. The majority of libraries described to date have used a solid support matrix for multiple-step syntheses. In this way the bench chemist can prepare large numbers of drug-like compounds for their use in various screening protocols in a time and resource effective manner. The main objective of this research proposal is to develop technologies for the discovery of PTP inhibitors as novel therapeutic drugs and to discover electroluminescent materials in application for organic light-emitting diodes (OLEDs) using combinatorial solid phase synthetic approach. Specific aims are: A. Rational design and synthesis of selective PTP inhibitors: 1. To identify the critical structural requirements of selective inhibitors of PTP1B, CD45, and cdc25 and to construct inhibitors that possess significant affinity for the active site as well as binding site of the particular receptor and to achieve desired activity through structure-function analysis. 2. To apply present, and also formulate new methodologies of combinatorial solid phase synthesis to prepare proposed PTP inhibitors. 3. To generate several new low molecular weight lead compounds as PTP inhibitors that are targeted selectively to specific receptors. B. Biological evaluation of PTP inhibitors: 1. To evaluate the activities of the synthesized inhibitors and correlate their biological properties with different receptors in order to design potent and selective inhibitors. 2. To compile useful structure-activity relationship data of interactions between PTP inhibitor and specific receptor. 3. To prepare a new generation of PTP inhibitors based on combinatorial synthesis using a rational combinatorial drug design approach, molecular modeling and quantitative structure-activity relationship (QSAR) studies C. Discovery of new phosphorescent emitters: 1. To design and synthesize electroluminescent organometallic materials in application for organic light-emitting diodes (OLEDs) using combinatorial approach. 2. To evaluate the electroluminescent properties of the identified hits. 研究期間：9808 ~ 9907
