Anion Binding of a Cyclopeptide-Derived Molecular Cage in Aqueous Solvent Mixtures

Abstract

A molecular cage consisting of two cyclic hexapeptides with an alternating sequence of (2S,4S)-4-aminoproline and 6-aminopicolinic acid subunits, covalently linked via three diglycolic acid subunits, interacts with a variety of inorganic anions in acetonitrile/water. In the respective complexes, the anion resides in a cavity between the two cyclopeptide rings where it interacts with six converging NH groups. The cage binds sulfate anions in acetonitrile/water, 2 : 1 (v/v) with a log Ka of 6.7, ca. 2.5 orders of magnitude stronger than an analogous bis(cyclopeptide) with only one linker whose sulfate affinity log Ka amounts to 4.3. The preorganization induced by the three linking units is thus beneficial for sulfate binding. In addition, these linkers cause the dissociation of the sulfate complex to have a substantial Gibbs free energy of activation ΔG≠ of 68.9 kJ mol−1 and they also seem to affect anion selectivity as illustrated by the different effects some anions produce on the 1H NMR spectra of the triply and singly-linked bis(cyclopeptides). Such anion binding cages represent promising scaffolds to mimic natural anion receptors such as the sulfate-binding protein.