合成胍基克流感與胍基零流感衍生物以改善親脂性

Synthesis of Guanidino-Oseltamivir and Guanidino-Tamiphosphor Derivatives with Improved Lipophilicity

李佩珊(Pei-Shan Lee)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.10737

摘要

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。

關鍵字

克流感 ； 零流感 ； 前驅藥物 ； 胍基

並列摘要

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.

並列關鍵字

tamiphosphor ； oseltamivir ； guanidine ； prodrug ； 150-cavity

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