Synthesis and Guest-Binding Properties of pH/Reduction Dual-Responsive Cyclophane Dimer

A water-soluble cyclophane dimer having two disulfide groups as a reduction-responsive cleavable bond as well as several acidic and basic functional groups as a pH-responsive ionizable group 1 was successfully synthesized. It was found that 1 showed pH-dependent guest-binding behavior. That is, 1 strongly bound an anionic guest, 6-p-toluidinonaphthalene-2-sulfonate (TNS) with binding constant (K/M−1) for 1:1 host-guest complexes of 9.6 × 104 M−1 at pH 3.8, which was larger than those at pH 7.4 and 10.7 (6.0 × 104 and 2.4 × 104 M−1, respectively), indicating a favorable electrostatic interaction between anionic guest and net cationic 1. What is more, release of the entrapped guest molecules by 1 was easily controlled by pH stimulus. Large favorable enthalpies (ΔH) for formation of host-guest complexes were obtained under the pH conditions employed, suggesting that electrostatic interaction between anionic TNS and 1 was the most important driving force for host-guest complexation. Such contributions of ΔH for formation of host-guest complexes decreased along with increased pH values from acidic to basic solutions. Upon addition of dithiothreitol (DTT) as a reducing reagent to an aqueous PBS buffer (pH 7.4) containing 1 and TNS, the fluorescence intensity originating from the bound guest molecules decreased gradually. A treatment of 1 with DTT gave 2, having less guest-binding affinity by the cleavage of disulfide bonds of 1. Consequently, almost all entrapped guest molecules by 1 were released from the host. Moreover, such reduction-responsive cleavage of 1 and release of bound guest molecules was performed more rapidly in aqueous buffer at pH 10.7.