合成新穎芳香碳醣苷衍生物並評估其生物活性

synthesis of novel c-aryl glycoside analogues and evaluation of their bioactivities

卡力亞納(ponnapalli, kalyana kumar)

指導教授 ： 林俊成

國立清華大學/理學院/化學系所/博士(2017年)

摘要

氧鍵結之醣苷類化合物廣泛存在於天然物中。然而，這些醣體於生物體中容易被醣水解酶或酸性條件下所降解，因此利用硫、氮或碳原子取代醣苷鍵的氧原子已被報導可增加醣苷鍵的穩定性，且與天然物的生物活性相似，具發展為治療藥物的潛力，其中，碳鍵結之醣苷分子具穩定性佳、分佈於自然界中细菌、昆蟲和植物體内等特性，引起科學家廣泛的興趣。文獻中常將多酚類化合物與一個以上的醣基結合，藉此增加二苯乙烯部分的水溶性，然而從自然界純化分離之碳鍵結醣苷分子含量稀少，且目前尚未發展出簡易效率高的合成策略，故其生理作用機制仍有待釐清。
第一部分利用微波輔助之Heck反應合成碳鍵結的二苯乙烯單醣及雙醣，此方法提供高選擇性與高產率的碳鍵結反式二苯乙烯醣苷合成方法，並應用於不同官能基修飾的碘化芳烴基醣體與不同位置取代的二苯乙烯之排列組合，同時完成C2對稱的碳鍵結反式二苯乙烯雙醣，而針對建構好的化合物進行人類SGLT2抑制活性測試，結果顯示其中三個類似物在 12 至 33 µM的濃度範圍中，對hSGLT2有明顯抑制效果。
第二部分發展4-(苯基-C-醣苷基)-1,2,3三唑之改進與多樣化合成策略，其中關鍵合成步驟為利用銅催化炔-疊氮環化加成反應 (copper(I)-catalyzed azide alkyne cycloaddition, CuAAC) 結合疊氮基醣苷化合物與不同取代之碳鍵結苯乙炔醣苷，而使用鄰苯二胺為CuAAC之配體可有效縮短反應時間並簡化純化過程，此方法適用於多種官能基且產率良好。透過交叉反應後得到一個小分子庫，對於β-galactosidase 及β-Galectin的抑制活性測試正在進行中。

關鍵字

芳香碳醣苷衍生物

並列摘要

O-Glycosides are integral part several natural products. However, the O-glycosidic bond is prone to cleavage under acidic condition and enzymatic in vivo conditions. Therefore several O-glycoside mimics were prepared to address this problem which includes S, N and C-Glycosides. These mimics generally will show similar biological activity compared to the natural compounds and thus can be considered as potential therapeutic targets. Among these glycomimetics C-Glycosides are particularly gained much interest because of their presence in number of natural products and stability under physiological conditions. Structural modification by glycosylation offers an attractive approach to increase the water solubility of polyhydroxy stilbenes. Even though C-glycosides are part of several natural products, the biological activity of C-glycoside stilbenes is not explored particularly due to rare occurrence and lack of straight forward synthetic methods.
In Chapter-1 we have developed microwave assisted Heck-coupling for the synthesis of mono- and bis-C-glycoside stilbenes using C-aryl glycosides and styrenes. This method provides exclusively C-glycoside trans-stilbenes with good yields. The developed Pd-catalyzed Heck-coupling method is successfully applied to various functionalized C-glycosyl aryl iodides and differentially substituted styrenes to deliver several C-glycoside trans-stilbenes with high selectivity. Synthesis of C-2 symmetric bis-C-glycoside-trans-stilbene is also accomplished. The obtained C-glycosyl trans-stilbenes were examined for human SGLT-2 inhibitory activity. Three of the analogues have shown hSGLT-2 inhibition in micro molar range (12 to 33 µM).
In Chapter-2, an improved and diversified synthesis for 4-(Phenyl-C-glycosyl)-1,2,3-triazoles was developed. The key step in the synthesis involves the copper catalyzed azide alkyne click chemistry between glycosyl azide and various substituted C-glycosylated phenyl acetylenes. Use of o-Phenylene diamine as a ligand in Copper catalyzed azide-alkyne click chemistry considerably shorten the reaction the time and allows simple purification. We have generated a small library to triazoles with broad substrate scope in terms of sugars. Interestingly each triazole analogue is having two free sugar units, one attached to the triazole nitrogen and other attached to the phenyl ring at C-4. The synthesized C-glycosylated triazole analogues were assayed for β-galactosidase and β-Galectin inhibition.

並列關鍵字

C-aryl glycoside

參考文獻

1. Werz, D. B.; Ranzinger, R.; Herget, S.; Adibekian, A.; von der Lieth, C.-W.; Seeberger, P. H. Exploring the Structural diversity of mammalian carbohydrates (″Glycospace″) by statistical databank analysis. ACS Chem. Biol. 2007, 2, 685−691.

2. Laine, R. A. Invited Commentary: A calculation of all possible oligosaccharide isomers both branched and linear yields 1.05 × 1012 structures for a reducing hexasaccharide: The isomer barrier to development of single-method saccharide sequencing or synthesis systems. Glycobiology 1994, 4, 759−767.

3. Nicotra, F.; Airoldi,C.; Cardona, F. Synthesis of C- and S- glycosides. Comprehensive Glycoscience. 2007, 1, 647-683.

5. Du, Y.; Linhardt, R. J.; Vlahov, I. R. Recent advances in stereo selective C-glycoside synthesis. Tetrahedron 1998, 54, 9913−9959.

9. Bertozzi, C. R.; Bednarski, M. D. Synthesis of C-glycosides; stable mimics of O- glycosidic linkages. In modern methods in carbohydrate synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood academic publishers: UK, 1996; pp. 316−351.