Pillararene-Based Pseudorotaxanes And The Construction Of Supramolecular Vesicles For Drug Delivery

For nearly half a century, supramolecular self-assembly has been a research hotspot in supramolecular chemistry. One of the most important aspects of self-assembly is the formation of threaded structures, such as rotaxanes, pseudorotaxanes and catenanes, due to their potential applications in nanotechnology and molecular machines. As the basic threaded structures, pseudorotaxanes have been a topic of great interest in recent years because they are not only the fundamental precursors for the preparation of novel supramolecular species, such as rotaxanes and catenanes, but also the prototypes of simple molecular machines. Therefore, the design and preparation of pseudorotaxanes with novel macrocyclic hosts and linear guests to form the templated-pseudorotaxane is highly desirable for both supramolecular chemistry and the fabrication of molecule-based devices. Meanwhile, the construction of supramolecular vesicles from novel pseudoamphiphiles through host-guest interactions, especially with stimuli-responsiveness, is of great interest and importance in application of biotechnology and biomedicine, particularly for drug delivery. Since reported in 2008, pillararenes, as a new class of macrocyclic hosts, have been focus of supramolecular chemistry. Owing to its unique rigid and symmetrical pillar architecture, pillararenes have been widely used as macrocyclic hosts in the construction of pseudorotaxanes with various guests. In this dissertation, we investigate the construction of pillararenes-based pseudorotaxanes and the fabrication of pillararenes-based pseudoamphiphiles for self-assembling into supramolecular vesicles for anti-cancer drug delivery. This dissertation mainly includes the following three parts:In the first part, a bis-urea-functionalized pillar[5]arene was synthesized and shown to form [2]pseudorotaxanes spontaneously with linear alkyl dicarboxylates in highly polar solvent DMSO, in which the hydrogen bonding interactions between the bis-urea hydrogens and dicarboxylate oxygens play an important role in stabilizing the novel [2]pseudorotaxanes alongside C-H-…π interactions.In the second part, The drug delivery system based on supramolecular vesicles that were self-assembled by a novel host-guest inclusion complex between a water-soluble pillar[6]arene (WP6) and hydrophobic ferrocene derivative in water has been developed. The inclusion complexation between WP6 and ferrocene derivative in water was studied by]H NMR, UV-Vis, and fluorescence spectroscopy, which showed a high binding constant of (1.27± 0.42)×105 M-1 with 1:1 binding stoichiometry. This resulting inclusion complex could self-assemble into supramolecular vesicles that displayed a significant pH-responsive behaviour in aqueous solution, which were investigated by fluorescent probe technique, dynamic laser scattering, and transmission electron microscopy. Furthermore, the drug loading and in vitro drug release studies demonstrated that these supramolecular vesicles were able to encapsulate mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which particularly showed rapid MTZ release at low pH environment. More importantly, the cellular uptake of these pH-responsive MTZ-loaded vesicles by cancer cells was observed by living cell imaging techniques, and their cytotoxicity assay indicated that unloaded vesicles had low toxicity to normal cells, which could dramatically reduce the toxicity of MTZ upon loading of MTZ. Meanwhile, MTZ-loaded vesicles exhibited comparable anticancer activity in vitro as free MTZ to cancer cells under examined conditions.In the last part, we firstly designed and synthesized two triazolophanes 1 and 2 based on phenyl-triazole. Both the crystal structure of triazolophane 1 and its 2D NOESY in DMSO-d6 demonstrated that it adopts syn-syn conformation both in the solid state and in solution. The crystal structure of triazolophane 2 and its 2D NOESY in CDCl3 demonstrated that it adopts anti-anti conformation both in the solid state and in solution. The 2D NOESY experiment in DMSO-^6 suggests that the intramolecular six-membered C-H…O hydrogen bonds also exist in solution. Subsequently, in order to evaluate the binding affinities of triazolophanes 1 and 2 with various anions in solution,1H NMR titration studies were conducted in CDCl3, where halides (F-, Cl-, Br-, and I-) and oxo-anions (H2PO4-, HP2O73-, HSO4-, AcO-, NO3-, and ClO4-) were investigated as their tetrabutylammonium salts. The results showed that triazolophane 1 has no binding affinities with the above investagted anions in solution. Whereas, titration experiments showed that triazolophane 2 was selective for fluoride ion. The intermolecular C-H-…F hydrogen bonds between 2 and F-are the main interactions.