Solubilization of cholesterol in aqueous solution by two β-cyclodextrin dimers and a negatively charged β-cyclodextrin derivative

Two beta CD dimers (linked by succinic acid, 2, or ethylenediaminetetraacetic acid, EDTA, 3, bridges) and a negatively charged monomer derivative of beta CD, 1, have been synthesized and their ability to solubilize cholesterol in aqueous solution was studied. The three compounds exhibit a great capacity in solubilizing cholesterol as, for instance, concentrations up to 6 mM of cholesterol were measured in the presence of 25 mM of 3. The phase-solubility diagrams of the two dimers exhibit A (L) type profiles while the monomer 1 follows an A (P) isotherm. The cholesterol/dimer complexes have 1:1 stoicheiometries while monomer 1 forms two complexes with molar ratios of 1:1 and 1:2 (cholesterol/1). The equilibrium constants are K (1:1) = (5.9 +/- A 0.3) x 10(4) M-1 and K (1:1) = (8.8 +/- A 0.2) x 10(4) M-1 for 2 and 3, respectively, and K (1:1) = 73 +/- A 19 M-1 and K (1:2) = 204 +/- A 65 M-1 for 1. The comparison of K (1:1)(3) with the product K (1:1) x K (1:2) (1) reveals that a chelate effect in binding the cholesterol by 3 exists. The structure of the cholesterol/3 complex was studied by ROESY experiments and by molecular dynamics simulations.