Molecular Clips that Undergo Heterochiral Aggregation and Self-Sorting

Wu, An‐Xin; Chakraborty, Arindam; Fettinger, James C.; Flowers, Robert A.; Isaacs, Lyle

doi:10.1002/1521-3773(20021104)41:21<4028::aid-anie4028>3.0.co;2-2

Cited by 122 publications

(172 citation statements)

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“…Given the well-known propensity for glycoluril and glycoluril dimer derived molecular clips to undergo self-association, 13a,26,28a,28d,30 we were surprised that the K s values for 1 and 2 were low (< 100 M −1 ). For purposes of comparison, the structures and self-association constants measured previously for compounds 1acid (K s = 1840 M −1 ) 26 and 2acid (K s = 41700 M −1 ) 13a which differ from 1a and 2a in the spatial orientation of their solubilizing groups are shown in Figure 4. Because the CO 2 − solubilizing groups of 1acid and 2acid are on their convex face, unfavorable carboxylate-carboxylate electrostatic interactions are avoided upon formation of dimers 1acid 2 and 2acid 2 .…”

Section: Resultsmentioning

confidence: 99%

“…These studies have resulted in the preparation of glycoluril dimer based molecular clips, 13 CB[n] analogues, 14 inverted CB[n], 15 nor-seco-CB[n], 16 bambus[n]urils, 17 CB[n] derivatives, 11a,12e,18 CB[n] dimers, 19 and acyclic CB[n]-type receptors. 12d,12g,12j,20 Recently, the Isaacs group used acyclic CB[n] containers as solubilizing excipients 21 for insoluble drugs and reported the influence of the nature of the solubilizing groups 22 and aromatic sidewalls 23 on their function.…”

Section: Introductionmentioning

confidence: 99%

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Acyclic cucurbit[n]uril-type molecular containers: influence of glycoluril oligomer length on their function as solubilizing agents

et al. 2015

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We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1 – 3) that all feature SO3− solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the x-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in π–π interactions with insoluble aromatic guests. Compounds 1 – 3 possess very good solubility characteristics (≥ 38 mM) and undergo only very weak self-association (Ks < 92 M−1) in water. The weak self-association is attributed to unfavorable SO3−•••SO3− electrostatic interactions in the putative dimers 12 – 42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, β-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin and ziprasidone, and PBS-1086.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acyclic cucurbit[n]uril-type molecular containers: influence of glycoluril oligomer length on their function as solubilizing agents

et al. 2015

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“…12,13 We found that 7 – 9 individually undergo self-assembly in CDCl 3 to yield homodimeric assemblies 8 2 and 9 2 and heterochiral homodimer (+)- 7 ·(−)- 7 (Figure 2b) driven by π–π interactions and H-bonds. We found that the three-component mixture 7 – 9 undergoes high fidelity self-sorting because the hypothetical heterodimers cannot satisfy the geometrical constraints of π–π interactions and simultaneously maximize the number of H-bonds formed.…”

Section: Self-sorting Systems Based On Self-recognitionmentioning

confidence: 85%

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

2014

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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.

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“…This phenomenon of selfsorting has been extensively investigated in hydrogen-bonded assemblies by Wu, Isaacs, and co-workers using a large range of classical building blocks, including the molecules reported in the previous paragraph, which, among them, can form a potentially very large number of partnerships. 246,247 However, from analysis of a mixture of nine building blocks in CDCl 3 , the authors have demonstrated that the association takes place preferentially between the established host-guest pairs.…”

Section: Hydrogen Bondingmentioning

confidence: 99%