臺灣博碩士論文加值系統

　　流感屬於上呼吸道的感染，過去曾爆發多起世界性的大流行造成數千萬人的死亡，此外在近幾年中也曾爆發出禽流感H5N1和2009年的新型流感H1N1，有此可知，流感病毒是不斷在進行突變，且隨時有造成大流行的可能性。目前最主要的抗流感藥物為克流感和瑞樂沙，並且在2007年中央基因體研究中心也開發出新一代的神經胺酸酶「零流感」，值得注意的是，胍基克流感GOA (14)和胍基零流感TPG (51)對流感病毒的神經胺酸酶有更好的抑制效果，但由於其衍生物的結構包含極性較大的胍基團，使得生物利用度較差而不易作為口服藥物。有鑒於此，我們設計出一系列GOA和TPG的衍生物，藉此提高其親脂性。

　　在第一個部分中，我們成功將HNAP修飾在GOA (14)的羧酸上以得到酯基前驅藥物GO－HNAP (27)，其可透過分子內離子對和親脂性基團以提高其親脂性，並且透過離體實驗也証明GO－HNAP (27)可藉由酯水解酶的作用而釋放出活性藥物GOA (14)。

　　在第二個部分中，我們將羥基胍基、烷基胍基和醯基胍基分別修飾於TPG (51)或其乙基單酯衍生物TPGEt (52)以得到一系列化合物，首先在親脂性的測試中，比較化合物 45和化合物 63的Log D可得知將取代基修飾於胍基的末端(terminal)上對親脂性的提升有較大的幫助。另一方面我們也進一步對衍生物進行抑制NA和抗流感病毒的活性測試，結果顯示烷基胍基化合物 62和63的抑制活性明顯下降許多，而醯基胍基化合物 71則失去活性，但值得注意的是，羥基胍基化合物 46在活性測試實驗中仍對NA有很好的抑制活性(IC50 = 6.1 nM)，然而在親脂性的實驗中，化合物 46因末端羥基的極性過大使得其親脂性只有些微的提升，有鑒於此，在未來可進一步針對羥基胍基進行保護基的修飾，期望透過此方式可有效的提高化合物的親脂性。

Influenza is a respiratory infection. It caused high mortality of annual epidemics and occasional pandemics in the past. Recently, the new type of mutated influenza viruses occurred. The outbreak of H5N1 avian flu and the new type H1N1 human flu in 2009 have increased public awareness of the potential for global influenza pandemics. Zanamivir and oseltamivir are main anti-influenza drugs targeting neuraminidase (NA). Another NA inhibitor tamiphosphor was developed by our group in 2007. Most importantly, guanidino-oseltamivir carboxylic acid (14, GOA) and gaunidino-tamiphosphor (51, TPG) are better inhibitors than oseltamivir against wild-type human H1N1 and avian H5N1 viruses. However, GOA (14) and TPG (51) have low oral bioavailability due to the high polarity of guanidine group. Therefore, my research focused on the synthesis of GOA (14) and TPG (51) derivatives with improved bioavailability.

In the first approach, GOA (14) was modified with 1-hydroxy-2-naphthoic acid (HNAP) as a possible ester prodrug GO-HNAP (27), which formed intramolecular ion-pair to increase lipophilicity. Besides, our preliminary study showed that GO-HNAP conjugate could release the active anti-influenza drug, GOA (14), by esterase catalyzed hydrolysis in rat plasma.

In the second approach, the guanidine group of TPG (51) or TPGEt (52) was modified as alkylguanidine, hydroxyguanidine and acylguanidine. Comparing the log D of compound 45 with compound 63, the modification at the terminal position of guanidine in compound 45 seemed to have better lipophilicity. In addition, these derivatives were subjected to inhibitory assays against influenza NA and viruses. The NA inhibitory activity of compounds 62 and 63 decreased, and compound 71 had no inhibition against NA. Although compound 46 showed better inhibition against NA (IC50 = 6.1 nM), it only slightly improved the lipophilicity. Therefore, modification of the N-hydroxyguanidino proup may lead to better lipophilicity.

目錄

謝誌 I
中文摘要 III
Abstract V
目錄 VIII
圖目錄 XI
表目錄 XIII
流程目錄 XIV
簡稱用語對照表 XV

第一章 緒論 1
　第一節　流行性感冒 1
　第二節　流感病毒簡介 2
　　2-1　流感病毒的組成 2
　　2-2　流感病毒感染宿主細胞的生命周期(life cycle) 3
　　2-3　流感病毒表面重要的膜蛋白 4
　　2-3-1　血球凝集素 (Hemagglutinin，HA) 4
　　2-3-2　神經胺酸酶 (Neuraminidase，NA) 6
　　2-4　離子通道蛋白M2 7
　第三節　流感藥物的開發 8
　　3-1　離子通道蛋白抑制劑 9
　　3-2　神經胺酸酶抑制劑 10
　　3-2-1　Zanamivir的開發 10
　　3-2-2　Zanamivir的改進 12

　　3-2-3　Oseltamivir的開發 14
　　3-2-4 Peramivir的開發 17
　第四節　抗藥性病毒的產生 18
第二章 結果與討論 21
　第一節　研究背景－零流感的開發 21
　第二節　利用分子內離子對(intramolecular ion-pair)增加分子的親脂性 23
　　2-1 設計概念 23
　　2-2 GO－HNAP (27)的合成 24
　　2-3 親脂性的測試與探討 27
　　2-4 離體培養活性檢測 29
　　2-4-1 活性測試的方法 29
　　2-4-2 抗流感活性的測試與討論 31
　　3-5 結論 33
　第三節　胍基前驅藥物 34
　　3-1 設計概念 34
　　3-2 羥基胍基化合物的合成 35
　　3-2-1 Oseltamivir衍生物的合成 35
　　3-2-2 Tamiphosphor衍生物的合成 37
　　3-3 抗流感活性和親脂性的測試與討論 40
　　3-4 化合物 31衍生物的合成 42
　　3-5 結論 43
　第四節　烷基胍基與醯基胍基化合物 44
　　4-1 設計概念 44
　　4-2 化合物 62和63的合成 46
　　4-3 化合物 71的合成 48

　　4-4 抗流感活性和親脂性的測試與討論 51
　　4-5 結論 53
　第五節　總結 53
第三章 實驗部分 55
　第一節　一般方法 55
　第二節　活性測試以及實驗步驟 56
　第三節　化學合成步驟以及結構鑑定 60
第四章 參考文獻 98
附錄化合物之核磁共振光譜 112


圖目錄

圖一、 　A型流感病毒的組成 3
圖二、 　病毒感染宿主細胞的生命週期與其抑制劑 4
圖三、 　禽流感與人流感病毒血液凝集素的受體末端結構 5
圖四、 　神經胺酸酶水解宿主表面唾液酸的示意圖 6
圖五、 　神經胺酸酶的作用機制 7
圖六、 　M2離子通道的作用機制 8
圖七、 　M2離子通道抑制劑可能的結合位置 10
圖八、 　神經胺酸酶與DANA (5)的共結晶 11
圖九、　 神經胺酸酶與GS4071 (13)的共結晶 16
圖十、　 GS4071 (13)與zanamivir (3)位於神經胺酸酶活性中心的空間結構示意圖 19
圖十一、 GS4071 (13)與tamiphosphor (18)位於神經胺酸酶活性中心的電腦分子模擬示意圖 21
圖十二、 GO－HNAP (27)的作用機制及酵素水解反應 24
圖十三、 利用鈀金屬對烯丙基化合物去保護的反應機制 25
圖十四、 MUNANA在NA活性測試中釋放螢光訊號的機制 30
圖十五、 CellTilter 96® Aqueous Non-Radioactive Cell Proliferation Assay 31
圖十六、 (a) GO－HNAP (27)在中plasma反應前的質譜MALDI－TOF; (b) 在plasma反應24小時後的質譜 33
圖十七、 (a) N1(綠色)與N9 (黃色)NA活性中心的三維晶體結構疊圖; (b) N8的NA活性中心與oseltamivir作用30分鐘(深藍)和3天(淺藍)的三維共結晶結構疊圖 44
圖十八、 N1的開放式構型與封閉式構型的三維晶體結構疊圖 45
圖十九、 o-Nitrobenzenesulfonamide在鹼性條件下去保護的反應機制 47



表目錄

表一、 主要的大流行流感 1
表二、 GS4071 (13)與Zanamivir(3)對各種神經胺酸酶病毒株的抑制能力參數 20
表三、 抑制神經胺酸酶、抗流感及細胞毒性 22
表四、 GOA (14)及GO－HNAP (27)的cLog P與 Log D 29
表五、 GO－HNAP (27)抑制NA以及抗流感病毒的活性 32
表六、 化合物31、45、46、47的抑制NA和抗流感病毒之活性 41
　　　 、cLog P與 Log D 41
表七、 合成硫脲試劑 68之反應條件探討 50



流程目錄

流程一、 化合物 23的合成途徑 25
流程二、 GO－HNAP (27)的合成途徑 26
流程三、 GO (20)與GOA (14)的合成途徑 27
流程四、 嘗試以BRCN試劑合成化合物 31 35
流程五、 化合物 34的合成途徑 36
流程六、 嘗試以硫脲官能基來合成化合物 31 37
流程七、 磷酸二乙酯試劑 37的合成途徑 37
流程八、 化合物 42的合成途徑 38
流程九、 化合物 46的合成途徑 39
流程十、 化合物 47的合成途徑 39
流程十一、 TPG (51)和TPGET (52)的合成途徑 40
流程十二、 化合物 53的合成策略ㄧ 42
流程十三、 化合物 56的合成途徑 43
流程十四、 化合物 53的合成策略二 43
流程十五、 化合物 62、63的合成途徑 47
流程十六、 硫脲試劑 68的合成途徑 49
流程十七、 化合物 71的合成途徑 51

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