功能胍基环糊精对羧酸类生物分子的选择键合研究

Molecular recognition and multicomponent assembly based on cyclodextrin derivatives is an essential part in the field of supramolecular chemistry. Compared to the mono-modified cyclodextrin derivatives, it is found that the ones possessing multiple substituents have improved binding abilities. In this proposal, we would like to design and synthesize some novel guanidinocyclodextrins with certain chemical composition and configuration, including the ones with the flexible alkyl chains and guanidiniocarbonylpyrrole group. Moreover, the geometrical changes upon complexation with a series of carboxylic biomolecules, such as the steroids of deoxycholic, chenodeoxycholic, and glycocholic acids, the anabolic products of 5-aminolevulinic and uric acids, as well as the quinolone antibiotics of nalidixic acid, ciprofloxacin, and levofloxacin, will be systematically investigated by the modern analytical methods. The binding mode and stability, as well as the synergistic effect arising from the non-covalent forces, such as the hydrophobic and electrostatic interactions, will be quantitatively studied by changing the concentration, temperature, and the numbers and types of substituent groups. The structure-activity relationship in these inclusion complexes will also be discussed from the view point of thermodynamics and kinetics. Meanwhile, the adverse effects of carboxylic biomolecules would be efficiently and selectively reversed and even eliminated both in vitro and in vivo via the supramolecular complexation strategy. Thus, we can envision that the present study will continue to energize the development of supramolecular chemistry.

环糊精的分子识别与组装是超分子化学的一项重要研究内容，而多取代环糊精较之单修饰环糊精具有更好的键合能力。因此，该项目拟设计和合成新颖的结构确定的胍基取代环糊精，包括柔性烷基链和羰基吡咯基团修饰的胍基环糊精衍生物，采用现代测试技术手段确定其构型，研究该类主体化合物与一系列有机羧酸分子（如脱氧胆酸、鹅去氧胆酸、甘胆酸等甾族类化合物、5-氨基酮戊酸和尿酸等体内合成代谢产物、以及萘啶酮酸、环丙氟哌酸、左氧氟沙星等喹诺酮类抗生素）选择键合的热力学和动力学性质。通过改变浓度、温度以及修饰基团的种类和数目考察分子的键合行为，以及疏水和静电等非共价相互作用在分子识别过程中的协同效应，从热力学和动力学的角度阐述分子识别的机理以及结构与功能之间的关系。同时，在细胞和小鼠活体水平上，利用超分子络合技术高效高选择性清除羧酸类生物分子，达到反转甚至消除其毒副作用的目的。这些对于超分子化学的发展具有重要的科学意义。

构建具有生物活性的超分子组装体已成为超分子化学研究的重要内容。根据项目申请书的要求，我们设计并合成了多种环糊精类大环超分子组装体，其中包括磷酸化酪胺修饰的β-环糊精、丙烯酸修饰的β-环糊精、微管靶向肽修饰的β-环糊精、以及其它带有正负电荷的环糊精衍生物等。采用核磁滴定、单晶衍射等测试技术确定了主‒客体复合物在液相和固相中的构型，通过紫外、荧光光谱、磷光光谱、等温量热滴定系统考察了该类环糊精与多种客体分子，包括稀土金属离子复合物、卟啉、胆酸等的分子识别、超分子组装和光物理行为，并进一步阐述了主客体分子间的组装性质及其在细胞成像、胆酸清除、肿瘤治疗等方面的生物应用功能。研究发现，全甲基化环糊精与卟啉分子之间的强键合作用，不仅可以有效增强卟啉的荧光发光强度，还可以提高卟啉单线态氧产生的能力，从而展现出优异的细胞（组织）成像、原药释放、光动力治疗等协同诊疗效果。在此基础上，我们还研究了其它大环分子，如葫芦脲和三苯胺基阳离子大环的分子组装性质和生物功能。这些研究成果这对于设计和制备新型生物功能超分子组装体具有重要的理论指导意义。