以呋喃并嘧啶化合物為極光激酶抑制劑之研究

Development of Furano[2,3-d]pyrimidine Compounds as Aurora Kinases Inhibitors

林振瑋(Chen-Wei Lin)

指導教授 ： 廖俊臣 ； 謝興邦

國立清華大學/理學院/化學系/博士(2009年)

摘要

本論文主旨在設計並合成可抑制極光激酶(aurora kinases)之呋喃并嘧啶化合物，希望以此發展為抗癌標靶藥物。由知識基礎設計(knowledge-based design)所篩選出之潛力化合物1為改進對象，利用循理性設計及混成設計，分別發展出潛力化合物20及48，再從化合物與Aurora-A之共結晶結構中，發現這兩個潛力化合物之蛋白質結構屬於DFG-out及類DFG-out構型，並以共結晶結構分析來解釋蛋白質構型與生物活性之關係。同時以高通量平行合成(high-throughput parallel synthesis, HTPS)方法來加快合成衍生物之速度，挑選出適當化合物加以進行結構上之修飾，在加入脲基及末端苯環後，成功地發現先導化合物183，並從共結晶結構分析瞭解其結構與激酶之作用力，導致蛋白質結構改變為DFG-in構型，而展現極光激酶抑制劑之特性。接著利用各種合成方法進行先導化合物之最優化，確認最好之側鏈結構為乙基苯脲苯，並得到化合物252，成功降低化合物之分子量及親油性，並提昇其細胞活性。

關鍵字

極光激酶 ； 呋喃并嘧啶

並列摘要

This dissertation is concerned with the development of furano[2,3-d]pyrimidine compounds as Aurora kinases inhibitors. Start from compound 1, we utilize rational drug design to synthesize two particular hits, compound 20 and 48. We analyze the co-crystal structures of two hits with Aurora-A, and observe the protein structures belong to DFG-out and DFG-out-like conformation. At the same time, we apply high-throughput parallel synthesis (HTPS) to accelerate the synthesis of analogues. Fortunately, we discover the lead compound 183 which was modified from compound 145 by forming the urea functionality and terminal phenyl group. We analyze the co-crystal structure of compound 183, and find the protein structure is DFG-in conformation. The variety does not only display in protein conformation but also improve the bioactivity. After lead optimization, we confirm the ethyl-phenyl-urea was the best side chain structure, and find compound 252 which successfully improve the cell bioactivity and reduce the molecular weight and lipophilicity.

並列關鍵字

Aurora kinase ； furano[2,3-d]pyrimidine

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