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

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 pi-pi interactions with insoluble aromatic guests. Compounds 1-3 possess very good solubility characteristics (>= 38 mM) and undergo only very weak self-association (K-s < 92 M-1) in water. The weak self-association is attributed to unfavorable SO3-center dot center dot center dot SO3- electrostatic interactions in the putative dimers 1(2)-4(2). Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, beta-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, ziprasidone, and PBS-1086.