||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 (例如 alkaloids, terpenes, polypropionates etc)，這些天然物分子甚少包含硼元素。正因如此，藥物開發單位在設計藥物時，通常沒有將硼元素納入考慮之列。其次,現階段含硼化合物的藥用機理尚未被完整地建立，因此許多知名藥廠對於含硼藥物的開發裹足不前。最後，由於多數含硼官能基(如：硼酸，硼酯)存在未鍵結之p軌域，使得這些官能基在許多常用的合成條件下與其他反應試劑發生不必要的副反應，使得含硼分子的合成難上加難。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公司目前正在進行第三期臨床試驗的 含硼化合物AN2690，證明了含硼藥物的開發是一個非常值得投資的新領域。 本研究計畫的兩個終極目標為, 第一: 利用 Ugi-四成分反應合成三個系列的含硼酸官能基之小分子化合物, 第二: 利用生化實驗以及細胞實驗來評估所合成之化合物是否具有抑制蛋白質水解酶功能與抗癌效果。
The vast majority of traditional medicinal chemistry approaches to drug development and biological probe constructions 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, by and large, 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 proposal is the development of novel boronic acids as therapeutic agents to target proteases and is outlined via two specific aims. Specific aim 1 describes the synthetic strategy used to construct libraries using the Ugi four-component reaction (Ugi-4CR), The phase-switch strategy will be applied as the purification method for these analogues. Specific aim 2 discusses cell-based cytotoxicity of the Ugi-4CR analogues on drug resistant pancreatic cancer cell lines as well as fluorogenic inhibitor screening assays. These assays will verify the hypothesis that boronic acids may serve as chemotherapeutic agents against drug resistant cancers by specifically targeting the cellular proteasome machinery. The proposed research program will span for 2 years. The first year of the program will mainly focus on synthesizing three Ugi libraries, and the second year will focus on conducting series of the biological evaluations of the synthesized libraries.