具有超大空腔的多联苯[n]芳烃新型大环的设计合成、对多肽/蛋白质的包结络合和应用

Macrocyclic hosts have played a vital role in the birth of modern supramolecular chemistry and its rapid development. Most of supramolecular macrocycles, for example cyclodextrins, calixarenes, cucurbiturils and pillararenes, have smaller cavities with diameter less than 1 nm, and thus can not interact with biologically important macromolecules such as proteins/peptides, DNA/RNA and polysaccharides. Therefore, it is significantly important and also a big challenge to design and synthesize macrocyclic hosts with giant cavities. In this project we will prepare a new family of synthetic receptors with nanosized cavities, [m]paraphenylen[n]arenes (m = 4-12, n = 3-6), which are made up of rigid and long dialkoxyl substituted [m]paraphenylenes. A series of water-soluble paraphenylenarenes with positive, negative and PEG groups will be synthesized, and their complexation behavior towards proteins and peptides will be investigated. The study is expected to clarify the driving forces, size-/shape-/charge-fit relationship and binding mechanisms between the water-soluble giant macrocycles and proteins/peptides, and to demonstrate the relationship between the host-guest structures and the thermodynamic data. Based on the recognition behavior, biomedical applications including the inhibition of aberrant aggregation of proteins and the increase of protein/peptide drugs will be tried. The study is hoped to build up new system of giant macrocyclic hosts, and therefore broaden the field of supramolecular chemistry.

大环主体分子在超分子化学的产生和发展过程中起到了举足轻重的作用，传统有机超分子大环（例如环糊精、杯芳烃、葫芦脲和柱芳烃等）的空腔直径通常小于1纳米，因此更适合识别小分子，无法对重要的生物大分子产生有效的包结络合。因此，设计构筑具有超大空腔结构的主体分子是一个有意义且具有挑战性的课题。本申请项目拟以刚性的二烷氧基多联苯（四联苯到十二联苯）为单体，通过亚甲基在烷氧基邻位相连接，构筑一类具有纳米尺度空腔的大环芳烃主体—多联苯[n]芳烃；并通过合成衍生，制备一系列阴离子、阳离子和PEG修饰的水溶性超大环。系统性研究这些水溶性超大环对蛋白质/多肽的分子键合行为，阐述主客体识别的匹配效应（尺寸、形状和电荷等）、驱动力、规律以及主客体结构和热力学参数之间的关系。进而在分子识别的基础上探索其在蛋白质阻聚和提高蛋白质/多肽药物稳定性等方面的应用。本项目有望建立和发展具有结构和功能特色的超分子超大环新体系。

大环主体分子在超分子化学的产生和发展过程中起到了举足轻重的作用，传统有机超分子大环（例如环糊精、杯芳烃、葫芦脲和柱芳烃等）的空腔直径通常小于1纳米，因此更适合识别小分子，无法对重要的生物大分子产生有效的包结络合。因此，设计构筑具有超大空腔结构的主体分子是一个有意义且具有挑战性的课题。在过去四年里，我们小组系统研究模块化合成拓展联苯[n]芳烃成环反应的合成方法学，进而制备多种具有不同电性的水溶性多联苯[n]芳烃超大环，并研究它们对蛋白质/多肽类分子的键合热力学、机理和驱动力，并探索其在生物医药和功能材料等领域的应用。