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

Mechanically interlocked molecules incorporating cucurbituril (CB[6]) as a molecular ‘bead’ and their supramolecular assemblies are described. An efficient synthesis of 1D, 2D and 3D polyrotaxanes with high structural regularity and molecular necklaces has been achieved by a combination of self-assembly and coordination chemistry. The functional aspects of these interlocked molecules and their supramolecular assemblies, including molecular machines and switches based on [2]rotaxanes, a 2D polyrotaxane with large cavities and channels, pseudorotaxane-terminated dendrimers, and interaction of pseudorotaxanes containing polyamines and CB[6] with DNA are also described.

Mechanically interlocked molecules incorporating cucurbituril and their supramolecular assemblies

A simple way to prepare cucurbit[5]uril is described. The macrocycles of the cucurbituril type are nearly insoluble in water. The solubilities of cucurbit[5]uril, decamethylcucurbit[5]uril and cucurbit[6]uril in hydrochloric acid, formic acid and acetic acid of different concentrations have been investigated. Due to the formation of complexes between cucurbit[n]urils and protons the solubility increases in aqueous acids. The macrocyclic ligands are able to form complexes with several organic compounds. Thus, the complex formation of the cucurbituril macrocycles with different amines has beenstudied by means of calorimetric titrations. The reaction enthalpy gives noevidence of the formation of inclusion or exclusion complexes. 1H-NMR measurements show that in the case of cucurbit[5]uril and cucurbit[6]uril the organic guest compound is included within the hydrophobic cavity. Decamethylcucurbit[5]uril forms only exclusion complexes with organicamines. This was confirmed by the crystal structure of the decamethylcucurbit[5]uril-1,6-diaminohexane complex.

Cucurbit[5]uril, Decamethylcucurbit[5]uril and Cucurbit[6]uril. Synthesis, Solubility and Amine Complex Formation

Cucurbituril as host molecule for the complexation of aliphatic alcohols, acids and nitriles in aqueous solution

The formation of cucurbituril complexes with amino acids and amino alcohols in aqueous formic acid studied by calorimetric titrations

The complexation of nonionicsurfactants and polyethylene glycols by the ligandscucurbituril, α- and β-cyclodextrin wasstudied in aqueous solution. All the examined guestmolecules form complexes with these ligands.Calorimetric titrations were performed to determinedirectly the stability constants and reactionenthalpies. The presence of an aromatic part innonionic surfactants leads to more stable complexeswith β-cyclodextrin than with the other ligands.If the surfactants contain no benzene group, theinteractions with α-cyclodextrin are strongercompared to other ligands. The chain length of thepolyethylene glycols has only an influence upon thevalues of the reaction enthalpy in the case ofα-cyclodextrin.

Cucurbituril and α- and β-Cyclodextrins as Ligands for the Complexation of Nonionic Surfactants and Polyethyleneglycols in Aqueous Solutions

Geometries, electronic properties and NMR-shielding of cucurbit[5]uril, decamethylcucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, and cucurbit[8]uril are investigated with DFT calculations. All molecules are highly symmetrical with a distinct geometric flexibility. In addition with a characteristic partial charge distribution these findings account for their chemical complex building ability.

H.-J. Buschmann

Papers

Cucurbit[5]uril, Decamethylcucurbit[5]uril and Cucurbit[6]uril. Synthesis, Solubility and Amine Complex Formation

Cucurbituril as host molecule for the complexation of aliphatic alcohols, acids and nitriles in aqueous solution

The formation of cucurbituril complexes with amino acids and amino alcohols in aqueous formic acid studied by calorimetric titrations

Cucurbituril and α- and β-Cyclodextrins as Ligands for the Complexation of Nonionic Surfactants and Polyethyleneglycols in Aqueous Solutions

Structure, Electronic Properties and NMR-Shielding of Cucurbit[n]urils