In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was dubbed "cucurbituril" by Mock and co-workers because of its resemblance to the most prominent member of the cucurbitaceae family of plants--the pumpkin. In the intervening years, the fundamental binding properties of CB[6]-high affinity, highly selective, and constrictive binding interactions--have been delineated by the pioneering work of the research groups of Mock, Kim, and Buschmann, and has led to their applications in waste-water remediation, as artificial enzymes, and as molecular switches. More recently, the cucurbit[n]uril family has grown to include homologues (CB[5]-CB[10]), derivatives, congeners, and analogues whose sizes span and exceed the range available with the alpha-, beta-, and gamma-cyclodextrins. Their shapes, solubility, and chemical functionality may now be tailored by synthetic chemistry to play a central role in molecular recognition, self-assembly, and nanotechnology. This Review focuses on the synthesis, recognition properties, and applications of these unique macrocycles.

The cucurbit[n]uril family

The supramolecular chemistry of cucurbituril, a synthetic receptor, is fascinating because of the remarkable guest binding behavior of the host. Studies in the field, however, have met with limitations, since the only species known was the hexameric macrocyclic compound, cucurbit[6]uril. Recently we synthesized its homologues, cucurbit[n]uril (n = 5, 7, 8), and derivatives. These new members of the cucurbituril family have expanded the scope further, and interest in them has grown enormously. This Account is a compilation of recent literature covering the syntheses of the homologues and derivatives, and their supramolecular chemistry.

Cucurbituril homologues and derivatives: new opportunities in supramolecular chemistry.

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Cucurbituril-Based Molecular Recognition.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Supramolecular chemistry has expanded dramatically in recent years both in terms of potential applications and in its relevance to analogous biological systems. The formation and function of supramolecular complexes occur through a multiplicity of often difficult to differentiate noncovalent forces. The aim of this Review is to describe the crucial interaction mechanisms in context, and thus classify the entire subject. In most cases, organic host-guest complexes have been selected as examples, but biologically relevant problems are also considered. An understanding and quantification of intermolecular interactions is of importance both for the rational planning of new supramolecular systems, including intelligent materials, as well as for developing new biologically active agents.

Binding Mechanisms in Supramolecular Complexes

Cucurbituril is a macrocyclic ligand with a rigid hydrophobic cavity. This cavity is accessible through two portals formed by six carbonyl groups. Ions are complexed by cucurbituril through ion dipole interactions. Uncharged organic compounds are included within the endolipophilic cavity of cucurbituril. Aromatic amines both have unpolar molecule parts and polar substituents. The complex formation of cucurbituril with o-phenylene diamine and 4-methyl aniline is investigated by proton resonance spectroscopy (1H-NMR) using DCl/D 2 O as solvent. The proton signals of the guest substances are shifted. This can be explained by the inclusion of the aromatic molecule parts of the model substances within the cavity of the macrocyclic ligand.

1H-NMR-Untersuchungen der Komplexbildung von aromatischen Aminen und Cucurbituril in wässrigen Lösungen

Die Erfindung betrifft textile Materialien, die mit Calixarenen der nachstehenden Formeln, welche chemisch oder physikalisch an dem textilen Material fixiert sind, ausgerustet sind Weiterhin betrifft die Erfindung Verfahren zu ihrer Herstellung und ihrer Verwendung

Mit calixarenen ausgerüstete textile materialien, verfahren zu ihrer herstellung und ihre verwendung

Cucurbituril is a macrocyclic host molecule which is nearly insoluble in pure water. It forms complexes with cations and organic hydrocarbons. Due to the complex formation with cations the solubility of cucurbituril increases. However, the complexes formed with different aromatic compounds are less soluble than the cation complexes. The formation of insoluble complexes of cucurbituril with different anilines, dichlorobenzenes and xylenes in aqueous solutions has been investigated. The complexation is not only influenced by the position of the substituents in the aromatic molecule, but also by salts and humic acids. In addition also the rate of complex formation decreases in the presence of salts and humic acids.

Einfluss von Salzen und Huminstoffen auf die Komplexbildung von Aromaten mit dem makrocyclischen Liganden Cucurbituril

α-Cyclodextrin and cucurbit[6]uril are macrocyclic ligands with nearly identical molecular properties. Both ligands possess nonpolar cavities with similar dimensions. They are able to include nonpolar molecules within their cavities. The main difference between both ligands is their solubility in water. An acceptable solubility for cucurbit[6]uril is only given in the presence of acids or salts. Due to the similarity of both ligands, the formation of mixed polyrotaxanes seems to be possible. The synthesis of statistically threaded α-cyclodextrin and cucurbit[6]uril on polyethylene glycol 2000 is verified using elemental analysis, 1H-NMR spectroscopy and differential scanning calorimetry. Under the experimental conditions used the number of threaded α-cyclodextrin molecules is higher compared with cucurbit[6]uril. However it is shown that the formation of mixed complexes is possible.

Polyethylene Glycol as String for the Simultaneous Complexation of α-Cyclodextrin and Cucurbit[6]uril

The invention relates to textile materials that are provided with calixarenes of the following formulas, which are chemically or physically fixed to the textile material. The invention also relates to methods for the production thereof and the use thereof.

Klaus Jansen

Papers

1H-NMR-Untersuchungen der Komplexbildung von aromatischen Aminen und Cucurbituril in wässrigen Lösungen

Mit calixarenen ausgerüstete textile materialien, verfahren zu ihrer herstellung und ihre verwendung

Einfluss von Salzen und Huminstoffen auf die Komplexbildung von Aromaten mit dem makrocyclischen Liganden Cucurbituril

Polyethylene Glycol as String for the Simultaneous Complexation of α-Cyclodextrin and Cucurbit[6]uril

Textile materials provided with calixarenes, method for the production thereof, and use thereof