Sequential inclusion of two berberine cations in cucurbit[8]uril cavity: kinetic and thermodynamic studies

Abstract

A combination of absorption and fluorescence spectroscopic studies with isothermal calorimetric titrations and stopped-flow measurements is a powerful way to reveal the thermodynamics and kinetics of inclusion complex formation with cucurbit[8]uril (CB8). The unique photophysical characteristics of berberine (B + ), a pharmaceutically important natural alkaloid, was exploited to distinguish the consecutive encapsulation processes, and to examine the confinement in CB8 cavity. The highly environment sensitive fluorescence lifetime of B + permitted of the selective detection of various cucurbituril complexes, and indicated to what extent the embedded guest is available for interaction with water. Highly stable 1:1 and 2:1 B + CB8 complexes were produced due to the release of the high energy water molecules from the CB8 interior, and the second binding step proved to be almost 3 times more exothermic. The favorable entropy change appreciably contributed to the driving force of 1:1 encapsulation. Contrarily, the embedment of the second B + in CB8 led to substantial entropy diminution. The kinetics of encapsulation was followed in real time by recording the fluorescence intensity change after rapid mixing of B + and CB8. No evidence was found for intermediates. The rate constants of (64 ± 9)×10 6 , and (5.0 ± 0.5)×10 6 M 1 s 1 were found for 1:1 and 2:1 associations, whereas 3.8 ± 0.6, and 0.6 ± 0.1 s 1were obtained for the rate constants of the reverse processes at 283 K, respectively.3

Assessment of Cooperativity in Ternary Peptide‐Cucurbit[8]uril Complexes

“…Both steps would thus be associated with large enthalpy–entropy compensation effects and opposite driving forces, that is, strongly enthalpy‐driven for the first step and strongly entropy‐driven for the second. In particular, the unfavorable positive enthalpy contribution (Figure 2 c, g) and the highly favorably entropy (Figure 2 d, h) for the second step are not realistic considering that CB[8] complexation is known to be enthalpically driven and entropically unfavorable 21, 22, 23. Overall, the considerations made in terms of fit error and of enthalpy–entropy compensation determined a range of acceptable K 1 / K 2 ratios between 0.2 and 6 for PheGly 2 and between 0.1 and 3.5 for PheGly 6 , which are highlighted in green in Figure 2.…”

A naphthalimide derived fluorescent sensor for solid-phase screening of cucurbit[7]uril–guest interactions

“…16–20 While CB[7] shows much promise as a host molecule in a variety of applications, it remains a significant challenge to rapidly screen compound libraries for guest molecules that bind to CB[7]. Indeed, CB[7]-guest interactions are typically analyzed using 1 H-NMR and isothermal titration microcalorimetry (ITC).…”

Directional Self‐Sorting with Cucurbit[8]uril Controlled by Allosteric π–π and Metal–Metal Interactions

“…While Scherman's guests 4 a and our Pt complexes 6 a – 6 c and 7 b form quaternary complexes with uneven charge distributions at the CB[8] rims, one can argue that stacked 2:2 assemblies are typically more stable than unstacked ones (see Figure a), as long as encapsulating the free moiety of one of the ditopic guests (labeled G in Figure a) into the water‐filled cavity of the binary complex (labeled H) is more favorable than switching from an even to an uneven distribution of charges. An interaction between a positive group and a CB[ n ] rim corresponds to an approximate 4 kcal mol −1 gain in total free energy (at least in the case of CB[7]), and the free binding energy of a guest such as berberine ( 1 ) into binary complex 1 ⋅CB[8] is approximately 8–9 kcal mol −1 . Therefore, a stacked 2:2 assembly will remain favorable over an unstacked arrangement even if a CB[8] rim can only stabilize one positive charge, as long as the repulsion between both charged units does not exceed 4–5 kcal mol −1 .…”