β‐Cyclodextrin Duplexes That Are Connected through Two Disulfide Bonds: Potent Hosts for the Complexation of Organic Molecules

Abstract

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.

Per-2,3-O-alkylatedβ-cyclodextrin duplexes connected with disulfide bonds

“…Their separation by HPlC could not be achieved under similar conditions as for non-methylated analogues (4). Interestingly, the analogous perallylated duplex was present as a single isomer 16 or 18; however, we were unable to attribute the one of the two possible structures to the product by means of NMr analysis.…”

“…We found that the distribution of resulting monomeric and dimeric species is highly influenced by the reaction conditions -the solvent system in particular. First we applied conditions that were similar to our recently published reports on non-alkylated cyclodextrin duplexes (2,4,5). Air oxidation of the disulfanyl derivative 11 was performed at 1 and 10 mM concentrations of compound 11 in the mixture of ethanol/H 2 O (1:1) using ammonium bicarbonate buffer at pH 9.…”

“…After completion of the reaction it was quenched with 1 M HCl (1 ml) and washed with ethyl acetate. The organic layer was washed with water, dried over MgSO 4 Table S1; 13 C-NMr, see Table S3. 6 I ,6 IV -Di-O-methanesulfonyl-6 II ,6 III ,6 V ,6 VI ,6 VII -penta-O-tert-butyldimethylsilyl-2 I , 2 II , 2 III , 2 IV , 2 V , 2 VI , 2 VII , 3 I , 3 II , 3 III , 3 IV , 3 V , 3 VI , 3 VII -tetradeca-O-methyl-β-cyclodextrin (5): To a solution of diol 3 (1.68 g, 0.883 mmol) and triethylamine (1.23 ml, 8.8 mmol) in anhydrous DCM (42 ml) at 0 °C under argon atmosphere mesyl chloride (0.420 ml, 5.4 mmol) was added dropwise, and the reaction mixture was further stirred for 1 h while allowing to warm up slowly to room temperature.…”

“…We have recently reported host molecules consisting of two cyclodextrin macrocycles connected with two or three disulfide bonds in a head-to-head manner (2)(3)(4)(5). These macrocyclic tubular receptors, coined cyclodextrin duplexes, possess significantly enlarged cavities (300-740 Å 3 ) as compared to native CDs and are capable of formation of inclusion complexes with a wide range of organic molecules in aqueous media with high binding affinities (K a ~ 10 5 -10 9 M −1 ).…”

A γ-cyclodextrin duplex connected with two disulfide bonds: synthesis, structure and inclusion complexes

“…We have recently described the syntheses and properties of new host systems composed of two α-CD or β-CD macrocycles linked with disulfide bonds. 25,26,[29][30][31] These tube-like molecules showed unusually high binding affinities (K a up to 10 10 M −1 ) to various organic compounds from hydrophobic α,ω-alkanediols 25,26 to fairly hydrophilic medium-sized molecules such as imatinib. 31 Now, we have turned our attention to a larger γ-CD homologue.…”