| Abstract
| - The cellular permeability of compounds can be enhanced in the presence of a host-[2]rotaxane (HR).The effective concentration of an HR is limited by the stoichiometry of the complex formation of theHR and the delivered compound. We speculate that a complex forms between the HR and a guest duringmembrane passage. To further explore the relationship between guest binding and guest delivery and toobtain more efficient delivery devices, we present, in this report, the first example of a cyclophane-[3]rotaxane (Cy3R), which has two wheels and a cyclophane as a blocking group. The properties of Cy3Rwere compared to a new cyclophane-[2]rotaxane (Cy2R) that has the same cyclophane pocket as Cy3Rbut only a single wheel. The second wheel of Cy3R can form additional noncovalent bonds, e.g., saltbridges, cation−π interactions or aromatic−aromatic interactions, with appropriately functionalized guests.We show by flow cytometric analysis that Cy3R transfers Fl-AVWAL (76%) and to a lesser degreeFl-QEAVD (26%) into live cells. The level of Fl-peptide within a cell is concentration dependent andlargely temperature and ATP independent, suggesting that a Cy3R·Fl-peptide complex passes throughthe cellular membrane without requiring active cell-mediated processes. Cy2R, on the other hand, formsweaker complexes and requires a higher concentration to transfer materials into cells. These resultsdemonstrate that the addition of a second wheel on a rotaxane can improve guest binding in varioussolvents and hence delivery through cellular membranes.
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