Stimuli Responsive Systems Constructed Using Cucurbit[n]uril-Type Molecular Containers

Abstract

ConspectusThis Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and π–π interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host–guest chemistry in water.We discovered that CB[n] homologues (CB[7] and CB[8]) display remarkably high binding affinity (Ka up to 1017 M–1) and selectivity (ΔΔG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host–guest systems. The CB[7]·adamantaneammonium ion complex, which is particularly privileged (Ka = 4.2 × 1012 M–1), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host–guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene–arylene foldamers and cationic calix[4]arenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves.Many guests display large pKa shifts within their CB[n]–guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB[7] toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB[7] from gold nanoparticles passivated with hexanediammonium ion·CB[7] complexes and thereby trigger cytotoxicity. CB[7] derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.

The Binding Interactions between Cyclohexanocucurbit[6]uril and Alkyl Viologens Give Rise to a Range of Diverse Structures in the Solid and the Solution Phases

“…While cucurbit [7]uril (CB7) is soluble in aqueous solution to millimolar levels, cucurbit [6]uril (CB6) and cucurbit [8]uril (CB8) are considerably less soluble in water. 2 Interestingly, CB6 derivatives with aliphatic equatorial substituents, such tetramethylcucurbit [6]uril 9 (Me4CB6), exhibit higher water solubility than CB6 itself.…”

Stimuli‐Responsive Cucurbit[n]uril‐Mediated Host‐Guest Complexes on Surfaces

“…In enzyme activity experiments, Fc-GOX showed a moderately reduced enzyme activity, but compared to covalently immobilized enzymes the enzymatic activity was similar. Furthermore they suggested a CB [7]-ferrocencemethylammonium pair as a replacement for the biotin-avidin pair, due to their strong binding properties of 10 15 M À1 , which is the first synthetic binding pair overcoming Figure 6. Velcro underwater adhesion system based on CB [7] and ferrocene interactions.…”

“…[11][12][13] These insights in CB[n] hostguest chemistry have recently led to developing bioanalytical and biomedical applications that are based on surfaceanchored CB[n] host-guest chemistry. While there are recent excellent reviews on CB[n] related host-guest complexation in solution, [11,13,[14][15][16] here we review in detail the latest progress of CB[n]-mediated host-guest complexes on surfaces with special attention to stimuli-responsive studies. Stimulusresponsive systems by means of pH, light or electrochemistry are attractive as such systems offer advantages such as dynamicity and reversibility, so that they are able to function as molecular machines or mimic molecular systems from nature.…”

Molecular dynamics of nor-Seco-cucurbit[10]uril complexes

“…Cucurbit[n]urils (CB[n]) are macrocyclic hosts composed of varying numbers of glycoluril units linked by methylene bridges [1][2][3]. The most common and commercially available CB[n]s are CB [5], CB [6], CB [7], and CB [8].…”