快速平行合成多岐異性的抗腫瘤新藥分子庫

Abstract

隨著工業發達而造成的環境污染，促使世界各國的癌症發生率和死亡率節節升 高。根據報導全世界每年大約有600萬人死於癌症，並且有近千萬癌症病人瀕臨死亡邊 緣。依據衛生署統計資料顯示，惡性腫瘤佔居2005年台灣十大死因之最，嚴重威脅國人 的健康，然則我國製藥業仍未有能力研發自己的新藥，是故，針對上述癌症疾病之治療 藥物及藥物發展技術研發，實為當務之急。通常每年全球上市的新化學單體之新藥約在 30種左右，大多為歐美先進國家所開發。製藥工業競爭力之泉源在於創新發明，由於新 藥的開發，需有比舊藥更好的生物活性資料，而且近年來對新藥的需求偏重於難治的慢 性病，不但藥效的判斷需要較長的時間，而且安全性、毒性等有關的試驗，也是要求長 期試驗，使得開發費用節節上升，如何建立更為有效的藥品開發技術則為日後努力的方 向。從以上的數據顯示，癌症是威脅人類健保以及消耗財力之勁敵，同時也顯示目前的 抗癌症藥物無法有效的克服癌症，因此本計劃將抗癌新物質研發，列為研究重心。利用組合式化學(Combinatorial chemistry)合成多樣化的小型有機分子庫，已經對傳 統藥物的研發造成很大的衝擊;由於持續不斷地發現新的蛋白質接受器和酵素與各種疾 病的關聯，如骨質疏鬆症，老年癡呆症，精神病，過敏….等，因此依據藥物和接受器或 酵素的相互作用來設計新型藥物，為目前新藥研發的主要途徑。組合式化學已經變成新 藥研發中不可或缺的一種工具，且提供了新藥研發一個有力的技術，能夠一次合成大量 多元化的化學分子庫；再配合高產量篩選(high throughput screening), 將對新藥開發產生 重大深遠的影響，並開啟一個全新的研究領域。 本研究計畫主要是利用微波組合化學來加速合成及設計多樣化的雜環分子庫為原則，以 開發新藥為目標，配合經濟效益之考量，繼續將有開發潛能的先導化合物最適化，同時 開創新生代的先導化合物。 在一些專利和文獻上曾經報導這類的化合物(quinolone, quinoxalinone)具有抗 腫瘤或抗病毒的生物活性; 由於這類藥物的重要性，使我們將這種具有活性的分子做為 先導藥物，策略性的建立於高分子支持物上，再進行雜環上取代基的變化，此類進行化 學官能基變化的方法，可以微調雜環模板上的電子及立體效應，增加藥物的活性:此種 方式在於尋求先導藥物的最佳化。 我們將再使用組合式新藥研發軟體(in vitro screening)決定的官能基變化和分 子庫的大小，並和國家衛生院生物技術與藥物研究組合作篩選其中可以被發掘成有潛力 的藥物。

The growing application of combinatorial organic synthesis on solid support has already been reflected in the rapidly increasing reaction types and synthetic strategies. It has been regarded as an important tool for the synthesis of a large number of pharmaceutically interesting compounds. In couple with high capacity screening systems, this technology may revolutionize the drug discovery process. However, solid-phase approach usually needs additional research and development time. We are focusing our research efforts on the liquid-phase combinatorial synthesis (LPCS) by the use of soluble polymer support to generate libraries. This macromolecular carrier, in contrast to an insoluble matrix, is soluble in most organic solvents and has a strong tendency for precipitation in particular solvents. After a reaction is complete, the product remains covalently bound to the support, and purification is generally carried out after precipitation simply by filtering and washing away the unwanted material. This method should decrease the difficulties of adapting established solution-phase precedents to polymer-supported reactions since reactions can be carried out in homogeneous solution. Furthermore, this method allows routine analytical methods (e.g. 1H, 13C NMR, IR, TLC) to monitor reaction progress and characterization without following cleave-&-analyze technique. Substituted quinolone and quinoxalinones are frequently found possessing broad biological activities, ranging from antiviral to antitumor. Therefore, a general method of rapidly synthesizing analogues of these scaffolds would be greatly advantageous and warrants further investigation for drug discovery. In order to improve the antiviral or antitumor profile of parent molecules, it is necessary to perform various synthetic modifications around the scaffolds. We will use our liquid-phase combinatorial technique to vary the positions and functionalization of substituent around these parent nuclei. Libraries compose of a diverse set of compounds can be possibly produced. We will use in vitro screening software such as Cerius and Catalyst from MSI to design more focusing libraries, which exhibit the required diversity because effective design of the libraries could reduce the number of molecules made and tested without reducing their diversity. High-throughput screening of our compounds will be cooperated with NHRI.