The rigid duplex cyclodextrin 6 composed of two α-cyclodextrin macrocycles connected with two disulfide bonds in “transannular” (C6I, C6IV) positions was prepared from partially debenzylated α-cyclodextrin 1 in four steps in 73% overall yield. In the last key step involving oxidative coupling of the thiol 5, predominance of the target duplex 6 can be attained under conditions of thermodynamic control. The structure of duplex cyclodextrin was established by MS as well as 2-D NMR methods and confirmed by a single-crystal X-ray analysis. The ability of the duplex cyclodextrin 6 to bind α,ω-alkanediols (C9−C14) and 1-alkanols (C9 and C10) was studied by isothermal titration calorimetry in aqueous solutions. The stability constants of the complexes gradually increase with the alkyl chain length and reach an unprecedently high value of K = 8.6 × 109 M−1 for 1,14-tetradecanediol. It was found that the doubly bridged dimer 6 exhibits higher binding affinity toward the series of α,ω-alkanediols than the singly bridged analogue 10 by about 2 orders of magnitude in K (M−1) or 3.1−3.3 kcal/mol in ΔG°, the enhancement being due to enthalpic factors. Theoretical calculations using DFT-D methods suggest that the enthalpic contribution stems from dispersion interactions.

Various sulfur-modified alpha-cyclodextrin (alpha-CD) derivatives formed ordered monolayers on gold surfaces as confirmed by water contact angle goniometry, electrochemistry, X-ray photoelectron spectroscopy, and atomic force microscopy measurements. Self-assembled monolayers (SAMs) of the adsorbates showed high polarity, uniform monolayer arrangement, and low charge transfer resistance. Electrochemical capacitance measurements were used to determine the binding affinity of aliphatic carboxylic acid salts with four, six, and eight carbon atoms. The nonmethylated cyclodextrin host-guest pairs showed 1-2 orders of magnitude higher binding constants on surfaces than in solution.

New tubular host molecules, which are composed of two β-cyclodextrin macrocycles that are connected through two disulfide bonds, have been prepared by the air-promoted oxidation of 6(I),6(IV)-dideoxy-6(I),6(IV)-disulfanyl-β-cyclodextrin in aqueous solution. This reaction leads to three products: monomeric intramolecular disulfide and two dimeric species, which are termed as "non-eclipsed" and "eclipsed" cyclodextrin duplexes. Oxidation at a concentration of the starting thiol of 0.1 mM gave the intramolecular disulfide as the major product whereas a concentration in the millimolar range afforded the dimeric species as the dominant products. The tubular structure of the "non-eclipsed" isomer was unequivocally determined by X-ray analysis. The binding affinities of the duplexes to a wide range of compounds, including fluorescent dyes and clinically used drugs Imatinib and Esomeprazol, were studied in water by ITC. For most guest compounds, the experimentally determined K(a) values were in the range 10(7)-10(8) M(-1). These binding affinities are significantly higher than those found in the literature for analogous complexes with native cyclodextrins. In cases of binding of neutral or anionic guest molecules cyclodextrin duplexes outperformed cucurbiturils. A complex between a duplex and Nile blue was used to investigate its ability to penetrate the cytoplasmic membrane of HeLa cells. We found that the complex accumulated in the cell membrane but did not pass into cytosol. Importantly, the complex did not decompose to a significant extent under high dilution in the cellular environment.

The compounds I-IV derived from α-D-cyclodextrin moiety by bridging and/or interconnecting with various patterns of disulfide bonds were chosen as models for the spectroscopic study of conformation of the disulfide bridge. The energy gap between the disulfide and cyclodextrin's electronic transitions allows us to investigate absorption and electronic circular dichroism spectra without disturbing spectral overlaps with amides or aromatic amino acids in peptides or proteins. Raman optical activity (ROA) spectra were measured and the bands due to S-S and C-S stretching motion identified. Comparison with the quantum mechanical calculations of simple models indicates that sense of disulfide twist follows sign of the measured S-S ROA band.