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, ziprasidone, and PBS-1086.

Figure 1

Structures of solubilizing molecular containers.

Figure 2

Structures of insoluble drugs used in this study.

Figure 3

Cross eyed stereoviews of the x-ray crystal structures of: a) 1ester, b) 2ester, c) 3b, d) 4b. Color code: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 4

Structures of comparison compounds.

Figure 5

Illustration of the packing of molecules of 3b into linear assemblies along the b-axis. Color code: C, gray; H, white; N, blue; O, red; S, yellow.

Figure 6

Plot of chemical shift versus [2a]. The solid line represents the best global fit of the data to a two-fold self-association model with K_s = 12 M⁻¹. Conditions: 20 mM sodium phosphate buffered D₂O, pD 7.4, room temperature. Key: H_a, ■; H_b, ●; H_c, ▲.

Figure 7

Idealized phase solubility diagrams.

Figure 8

Phase solubility diagrams created for: a) 1 – 4 with β-estradiol, b) 1b and 4b with camptothecin, and c) 1a, 2, 3, and 4a with camptothecin. Conditions: 20 mM sodium phosphate buffer, room temperature, pD 7.4. Symbols: 1a, ◆; 1b, ◇; 2a, ■; 2b, □; 3a, ▲; 3b, △; 4a, ●; 4b, ○. Data points colored red were not used for linear fitting.

Scheme 1

Synthesis of new containers 1 – 3. Conditions: a) TFA/Ac₂O (1:1), 70 °C, 5; b) TFA/Ac₂O (1:1), 70 °C, 6; c) TFA, paraformaldehyde, reflux; d) 1CE, MeSO₃H, 10°C to 23 °C.