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

Abstract

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.

Glycoluril‐Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water

“…Compound 1 was prepared as described previously. [20] Figure 2b,c shows two views of the electrostatic potential surface of an MMFF model of 1 . As expected, the ureidyl C=O groups of the glycoluril building blocks are regions of highly negative electrostatic potential (≈ −200 kcal mol −1 ) due to the convergence of the neighboring C=O groups and the four SO 3 − groups.…”

“…camptothecin and PBS-1086) although not as potently as M2 . [20] Around this time we were approached by the organizers of the SAMPL5 challenge who requested a blinded data set of host•guest binding constants. [14] Given the earlier use of macrocyclic CB[n] and acyclic CB[n]–type containers in the SAMPL challenges [14,15] it seemed appropriate to study the host-guest recognition properties of glycoluril dimer molecular clip 1 for this purpose.…”

“…We determined that 1 only undergoes weak dimerization in water (K s = 6 M −1 ), presumably due to the presence of unfavorable sulfonate-sulfonate electrostatic interactions in the putative dimer (Figure 2a). [20] The largely monomeric nature of 1 allows it to realize its full binding affinity toward appropriate guests in water. We report herein that 1 is a remarkably potent and selective receptor in aqueous solution for aromatic cations over aliphatic cations.…”

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors

“…Additionally, the internal molecular recognition surfaces of acyclic CB[n] can be tailored by synthetic modifications. In a series of papers, we have explored the influence of the nature of the solubilizing groups, 38 the aromatic walls, 37 and the length of the central glycoluril oligomer 39 on the solubilizing ability of acyclic CB[n]-type containers. We have found that acyclic CB[n] display higher binding affinity (range: 10 3 – 10 6 M −1 ) than HP-β-CD (range: 10 2 – 10 4 M −1 ) toward a panel of 19 insoluble drugs which means that lower concentrations of acyclic CB[n] are needed to formulate a given concentration of drug.…”

Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge

“…It has three characteristic structural features; (1) a central glycoluril oligomer induces curvature, (2) terminal aromatic walls enhance binding to drugs with aromatic rings, and (3) sulfonate arms enhance solubility [40, 41]. The Isaacs group measured the binding affinities CBClip and ten guest molecules.…”