甘草素與氮醣之研究:I 合成甘草素衍生物作為抗SARS冠狀病毒試劑II 氮醣之合成與醣化合物在水相中之反應

Study of Glycyrrhizic Acid and Azasugars:Synthesis of Glycyrrhizic Acid Derivatives as the Anti-SARS-CoV Agents Synthesis of Azasugars and the Reactions of Saccharides in Aqueous Solution

簡崇訓(Chong-Shun Jian)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.00602

摘要

這篇論文主要分為兩部份：第一部份，我們已經成功合成甘草素衍生物作為對抗嚴重性呼吸症候群(severe acute respiratory syndrome，SARS)冠狀病毒複製的試劑。在第二部份、我們已經成功的合成氮醣化合物的骨架及發展出一些醣類分子在水相中的反應。
甘草素在生物體內具有相當廣泛的應用價值，例如：抗免疫、抗過敏、抗衰老、抗氧化和抗癌等。然而，甘草素對於生物體內的作用機制尚不明確。最近國外學者發現甘草素能夠抑制SARS冠狀病毒的複製，但是所需的劑量太高。因此對於甘草素進行化學修飾，希望能找到更有效對抗SARS病毒的甘草素衍生物。甘草素的結構主要分為兩個部分：一個部份為18β甘草酸而另一個部份為雙葡萄糖酸的部份，我們已經在甘草酸上成功偶合重要的醣類分子(唾液酸、葡萄醣胺)，得到化合物25和26，初步的篩選結果，我們發現到化合物25在20 μM濃度即可抑制SARS冠狀病毒對Vero E6細胞的感染，比甘草素(EC50=1mM)的效果明顯改善。
在第二部份，由於抗生素的抗藥性問題日趨重要，因此對於抗生素藥物的開發也是刻不容緩。轉醣是細菌合成細胞壁的一個關鍵酵素，因此我們希望能夠合成出有效的轉醣的抑制劑。而在這個部份，我們成功合成出氮醣分子骨架。在水相反應中，我們也發現到了N-乙醯基葡萄醣胺分子會在碘和氨水溶液中進行降解反應。此外，我們也發現到了醣類分子能夠有效和一級胺類分子連結，形成穩定的醯胺鍵，希望這些水相反應能夠有效應用於醣類化學合成。

關鍵字

氮醣 ； 甘草素

並列摘要

This thesis consists of two parts. In the first part, we already synthesize glycyrrhizic acid derivatives as the antiviral angents against severe acute respiratory syndrome corona virus (SARS–CoV) agents. In the second part, we synthesize azasugars and explore some reactions of saccharides in I2/NH3 aqueous solution.
Glycyrrhizic acid is known to exhibit wide range of biological activities, for example, anti–inflammatory, anti–allergic, anti–dote, antioxidation and anti–tumor activities. However, the mechanism of glycyrrhizic acid in vivo is still unclear. It is reported that glycyrrhizic acid has the activity to inhibit the replication of the SARS coronavirus,but the inhibition concentration is still high. Consequently, it is desirable to find better SARS–CoV inhibitors by modification of glycyrrhizic acid. The structure of glycyrrhizic acid consists of two parts, one is 18β glycyrrhetinic acid and the other is disaccharide. I carried out a research work to replace the disaccharide part by other important saccharides, e. g., sialic acid and GlcNAc, to obtain compounds 25 and 26. By comparision of the inhibitory activity of glycyrrhizic acid (EC50 =1mM), we found that compound 25 greatly improves the inhibitory activity (EC50 = 20 μM) against the infection of SARS coronavirus on Vero E6 cells.

Antibiotic resistance is a serious problem in many diseases. transglycosydase is one of enzyme in essential of bacterial cell wall synthesis. We desire to synthesize azasugars as transglycosydase inhibitors. In this part, we have synthesized the backbone structure of azasugars. In another approach, we found GlcNAc was degraded by I2 and ammonia water. We also found that saccharides can be linked with primary amines in aqueous solution by the promotion of I2. This novel type reaction is potentially useful in carbohydrate chemistry, such as in preparation of glycopetide in future.

並列關鍵字

Glycyrrhizic Acid ； Azasugars

參考文獻

1.http://altmed.od.nih.gov/，美國國家衛生研究院下之國立互補與替代醫學研究中心(NIH for Complementary and Alternative Medicine)官方網站。

24.Tsang, K. W.; Ho, P. L.; Ooi, G. C.; Yee, W. K.; Wang, T.; Chan-Yeung M.; Lam, W. K.; Seto, W. H.; Yam, L. Y.; Cheung, T. M.; Wong. P. C.; Lam, B.; Chan, J.; Yuen, K. Y.; Lai, K. N. N. Engl. J. Med, 2003;348, 197-1985.

77.Hayes, W.; Osborn, M.; Osborne, S.; Rastall, A.; Romagnoli, B. Tetrahedron. 2003, 59, 7983-7996.

13.Agarwal, R.; Wang, Z. Y.; Mukhtar, H.; Nutr Cancer 1991, 15,193.

8.Wang, Z. Y.; Nixon, D. W. Nutr. Cancer. 2001, 39,.