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    Title: 含硼之蛋白?體抑制劑的設計,合成,以及生物活性之測試
    Other Titles: Design, Synthesis, and Biological Evaluations of Boron Containing Proteasome Inhibitor
    Authors: 潘伯申
    Contributors: 淡江大學化學學系
    Keywords: 硼元素;硼酸;類胜?衍生物;Ugi四單元反應;蛋白?體;胰臟癌
    Date: 2011
    Issue Date: 2012-05-02 09:50:57 (UTC+8)
    Abstract: 絕大多數傳統藥物開發的方法,都將藥物分子的組成成份侷限在下列幾種元素當中:碳、氫、氧、氮、硫以及鹵素。至於硼則甚少被包括於其中。其原因可歸納為以下幾點:首先, 藥物分子的設計,通常是依據天然物分子結構而衍生的,而這些天然物分子中甚少包含硼元素。正因為如此,製藥單位在設計藥物時,通常沒有將硼元素納入考慮之列。其次,現階段製藥單位對於含硼化合物的藥物特性並不熟悉,也因此在之前許多知名藥廠對於含硼藥物的開發裹足不前。最後,最常見的硼碳鍵難以在多元的化學反應條件下生存,也使得開發含硼藥物難上加難。然而,近來研究發現含硼藥物分子對於其所作用之生化目標,具有高度選擇性及高度活性等優點。也基於這些優點,使得許多藥廠摒棄成見,逐漸積極投入含硼藥物之開發。以剛經由美國食品藥物管理局審核上市的硼酸抗癌藥物bortezomib(Velcade),以及Anacor公司的成功案例為例(http://www.anacor.com),可以證明含硼藥物的研發,是一個非常值得開發的新領域。 本研究將以蛋白酶體(proteasome)為抑制目標,合成六大類環狀含硼酸之類胜肽衍生物 (cyclic peptoids containing boronic acid)抑制劑 。本計畫兩項具體之目標分別為, 第一,利用 Ugi 四單元反應法合成六類結構不同的環狀含硼酸之類胜肽衍生物分子庫 ; 第二,本計畫將利用胰臟癌細胞以及生化活性實驗篩選出具有抗癌活性之化合物。透過一系列之生物/生化實驗我們將能夠驗證所設計以及合成之環狀含硼酸之類胜肽衍生物是否能夠因為抑制蛋白酶體的活性而進一步的殺死胰臟癌細胞。
    The vast majority of traditional medicinal chemistry approaches to drug development are typically based on a very limited number of elements: Carbon, Hydrogen, Oxygen, Nitrogen, Halogens, and Sulfur (CHONXS). Boron has been a vastly underutilized element in drug discovery efforts and pharmaceutical products for a variety of reasons. First, medicinal chemists take their design cues from nature (e.g., using biologically active proteins, alkaloids, terpenes, polypropionates, and other natural products as models), and there is a decided dearth of naturally occurring boron-containing molecules upon which to base rational drug design. Second, the pharmaceutical industry’s lack of experience with boron containing drugs has hampered advances in this area, as, unlike more conventional agents, there is limited understanding of physico-chemical properties, pharmacokinetic attributes, and safety of these agents. Finally, in a point to be addressed in the current proposal, boron-based compounds have been historically difficult to synthesize, owing to the sensitivity of the carbon-boron bond to a host of common organic reagents. The focus of this research is the development of novel cyclic peptoids containing boronic acids as therapeutic agents to target the 20S proteasome and is outlined via two specific aims. Specific aim 1 describes the synthetic strategy used to construct cyclic peptoid libraries utilizing the Ugi four component reaction (Ugi-4CR). Specific aim 2 discusses cell-based cytotoxicity of the peptoid analogs on drug resistant pancreatic cancer cell lines as well as 20S proteasome biochemical activity assays. These assays will verify the hypothesis that cyclic peptoids containing boronic acids may serve as chemotherapeutic agents against drug resistant cancers by specifically targeting the cellular proteasome machinery.
    Appears in Collections:[化學學系暨研究所] 研究報告

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