钯催化生物正交偶联反应对细胞表面聚糖的功能化研究

Glycans at the cells surfaces play important roles in signaling, cell adhesion and differentiation processes, especially during embryonic development. So develop highly efficient bioorthogonal reaction become a hot research area in recent years, as this strategy offers a new avenue for labeling, visualizing and functionalization biomolecules in vivo without the requirement of genetic manipulation. This project will focus on developing palladium catalyzed bioorthogonal reaction (Heck and Sonogashira reaction) with high efficiency and low cytotoxicity. Based on this approach, different unnatural monosaccharide containing bioorthogonal reporter (alkene or alkyne) will be installed to cell surface firstly by metabolic oligosaccharide engineering (MOE). Then different molecular probe with diverse functionality (such as fluorescent probe, 19F-NMR probe, MRI probe and drug release probe) will be introduced by palladium catalyzed bioorthogonal cross coupling reaction, which enable imaging and functionalizing of glycans at the cell surface. Finally, comprehensive analysis of this bioorthogonal reaction with other type of bioorthogonal reaction such as click chemistry will be performed. By proceeding this project, a higher efficient and more bio-compatible method will be developed to visualizing and functionalizing of glycans at the cell surface, which will provide a better way to understanding the processes of cell surface glycans at the molecular level.

细胞表面聚糖在信号传导、细胞粘附、分化，尤其是胚胎发育过程中发挥着至关重要的作用。发展高效的生物正交反应对细胞表面聚糖进行可视化及原位功能化是近年来糖生物学领域的热点。本项目拟发展高效、低毒的钯催化生物正交偶联反应，包括Heck反应和Sonogashira反应。首先将含有报告基团的非天然单糖通过非天然糖代谢工程 (MOE) 表达到细胞表面。再经钯催化的生物正交偶联反应高效的将一系列结构新颖的小分子功能探针( 如荧光、19F-NMR、MRI及药物释放探针)与含有报告基团的细胞表面聚糖共价连接，实现对聚糖成像分析及功能化研究。进一步将上述反应与其他类型生物正交反应(如点击化学)进行系统比较，探讨该类生物正交反应在细胞表面聚糖功能化研究中所具有的潜在优势。本项目的开展将提供一种效率更高、生物兼容性更好的细胞表面聚糖功能化研究工具，并将极大促进人们在分子水平上理解细胞表面糖基化的生物功能。

细胞表面聚糖在信号传导、细胞粘附等过程中发挥着重要作用。本项目以发展高效的钯催化生物正交偶联反应对细胞表面聚糖进行原位功能化为目标，合成了一系列小分子功能探针，通过系统的条件筛选，成功的将钯催化的偶联反应用于细胞表面聚糖的原位标记。同时，我们致力于开发新型的功能荧光探针分子，我们与合作者基于四苯乙烯骨架合成了两类聚集诱导荧光探针，并成功实现了对生物硫醇的比率型检测以及水相条件下对碘离子/汞离子的序列型检测。在此基础上，我们通过对联二萘酚骨架进行结构修饰，成功合成了一系列手性聚集诱导荧光分子并将其应用于金属离子检测。此外，我们与合作者从对2,2-二氰基乙烯基苯出发进行结构修饰，构建了一系列全彩有机小分子荧光化合物并对其发光行为进行了深入探讨。最近，我们对基于二乙氨基香豆素骨架的两类香豆素衍生物的发光行为开展了系统研究，揭示了其同质多晶、刺激响应、光波导等发光特性。