Investigation On Shape-persistent Macrocycles And Molecular Cages As Artificial Transmembrane Channels

Artificial transmembrane channels are a class of synthetic molecules that are able to mimic the structures and/or functions of natural ion channels. Over the recent years, a variety of synthetic transmembrane channels have been investigated, including small organic molecules, peptide mimics, macrocyclic compounds, polymers and metal-organic frameworks. Their potential applications have been explored in drug delivery, signal transduction, molecular recognition, and so forth. However, reports of transmembrane channels based on shape-persistent macrocycles and molecular cages are still rare.Herein, a range of shape-persistent macrocycles and molecular cages have been synthesized via dynamic covalent chemistry(DCVC). The channeling activities and mechanisms of the resultant molecules in the transmembrane transportations of ions and small molecules have been examined in stable vesicles formed by lipid bilayer. The transportation of small molecules by the molecular cage has also been verified in vitro in HEK 293 T cells.First, a series of shape-persistent phenylene-vinylene macrocycles and phenylene-ethynylene macrocycles substituted with various side chains have been synthesized by DCVC of alkene and alkyne metathesis respectively. The performances of the obtained macrocycles in the transportation of proton and small molecules have been compared, which shows that the length and polarity of the side chains have significant effects on the ionophore formation and the mass transport efficiency. Macrocycles with higher aggregation facilitate faster ion passage across the lipid bilayer.Finally, based on the findings from the rigid 2-dimensional macrocycles, a series of shape-persistent 3-dimenstional molecular cages(also called covalent organic polyhedrons or COPs), have been designed and prepared. The resultant porphyrin-embedded arylene-ethynylene cages with different substituents have been investigated as transmembrane channels for cations, anions and small molecules. It has been found that the molecular cages with hydrophobic substituents can insert into lipid bilayer and mediate the transmembrane transportation of ions and small molecules(e.g. calcein). It has also been revealed that longer hydrophobic alkyl chains mimicking lipid tails promote higher channeling efficiency of the cage, while shorter and/or more polar side chains impair such activity. Kinetic analysis shows linear correlation between the rate of proton transport and the concentration of the cage with long alkyl side chains(Cage3), suggesting the active species of Cage3 is likely a monomeric cage. Moreover, Cage3 with C70 encapsulated in the internal cavity demonstrates a channeling activity comparable to the control level, indicating that ions are likely transported through the internal cavity of the cage. The transportation of small molecule by the molecular cages has also been verified in vitro in HEK 293 T cells, suggesting these highly stable rigid cages hold good potential for the applications of signal transduction and drug delivery as artificial transmembrane channels.