Deep Inside Cucurbiturils: Physical Properties and Volumes of their Inner Cavity Determine the Hydrophobic Driving Force for Host–Guest Complexation

Abstract

Cucurbit[n]urils (CBn) bind guest molecules through a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the inner cavity. Investigations with solvatochromic probes in CB7 reveal that the polarity of the cavity resembles that of alcohols (e.g., n‐octanol), while its polarizability (P=0.12) and apparent refractive index (nD=1.10±0.12) are extremely low, close to the gas phase. The calculated molecular quadrupole moments of CBs are extremely large (Θzz=−120 to −340 Buckingham). A survey of reported binding constants of neutral guests and hydrophobic residues that form 1 : 1 inclusion complexes with CB6, reveals a preferential inclusion of C3–C5 residues in its cavity. The largest guests which show non‐negligible binding contain 7 heavy atoms (excluding hydrogen). For CB7, the strongest binding is observed for guests with adamantyl (10 heavy atoms) and ferrocenyl groups (11 heavy atoms), while the largest guests known to be complexed are carborane and the adduct of two pyridine derivatives (12 heavy atoms). The evaluation of different volumes shows that the most meaningful cavity, namely that responsible for binding of hydrophobic residues, is confined by the planes through the oxygen carbonyls. The volume of this inner cavity follows the formula V/Å3=68+62(n−5)+12.5(n−5)2, affording representative cavity volumes of 68 Å3 for CB5, 142 Å3 for CB6, 242 Å3 for CB7, and 367 Å3 for CB8. The volume of the 2 bond dipole regions is comparably smaller, amounting, for example, to 2×35 Å3 for CB6. The analysis of packing coefficients for representative sets of known guests with clearly defined hydrophobic binding motifs reveals average values of 47 % for CB5, 58 % for CB6, 52 % for CB7, and 53 % for CB8, which are well in line with the preferred packing (“55 % solution”, see S. Mecozzi, J. Rebek, Chem. Eur. J. 1998, 4, 1016–1022) in related supramolecular host–guest assemblies. The driving force for binding of hydrophobic guests and residues by CBs is interpreted in terms of the unimportance of dispersion interactions (owing to the low polarizability of their cavity) and the dominance of classical and nonclassical hydrophobic effects related to the removal of very‐high‐energy water molecules (2 for CB5, 4 for CB6, 8 for CB7, and 12 for CB8) from the cavity.

Kinetics and Thermodynamics of Berberine Inclusion in Cucurbit[7]uril

“…25 Although hydrophobic and charge-dipole host-guest interactions contribute to the stabilization of the inclusion complex, the strongly negative binding enthalpy (Table 1) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 hydrophobic core of the macrocycle. 30,31 CB7 contains on average 7.9 water molecules, which do not form energetically stable hydrogen bond network and their electrostatic interactions are weaker in the interior of the nonpolar, extremely nonpolarizable host than in the bulk solution. 32 The water molecules expelled by B + from CB7 reassemble in the bulk leading to substantial enthalpy gain.…”

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

“…Recently there has been much interest in using cucurbit[n]urils (CB) as molecular delivery containers that enhance drug delivery to the intended target by protecting the drug from attack and degradation by biological agents. [30][31][32] [Saleh 2013, Nau 2011, Walker 2011] Many drugs have been found to be encapsulated within the cavity of CB, particularly cucurbit [7]urils, CB [7], and it may that TPZ or some its analogues may also form inclusion complexes with CB [7]. If this were so, then the formation of TPZ@CB [7] inclusion complexes may be beneficial in delivering increased quantities of TPZ compared to free TPZ to tumours and so increasing anti-cancer efficacy within the tumour.…”

“…31,40 [Nau 2011, Fong 2017 In this study the configurations of the TPZ@CB [7] were varied from the "external configuration" to the "internal configuration" using the SMD solvent model. The SMD model calculates the solvation free energy as electrostatic component and the non-electrostatic component, ΔG CDS,water .…”

Effect of host–guest complex formation on the fluorescence of 6-methoxy-1-methyl-quinolinium cation with 4-sulfonatocalix[4]arene: utilization as a fluorescent probe for the study of difenzoquat binding

“…Recent studies demonstrated that the release of high-energy water from cucurbiturils plays a decisive role in the binding affinity [27][28][29].…”