The Skaggs Institute
for Chemical Biology

Scientific Report 2007

The Inner Space of Molecules

J. Rebek, Jr., D. Ajami, M. Ams, E. Barrett, A. Carella, T.J. Dale, N. Gombosuren, R.J. Hooley, J.-L. Hou, T. Iwasawa, E. Mann, L. Moisan, S. Odermatt, F. Pinacho Crisostomo, P. Restorp, S. Shenoy, M. Schramm, C. Turner, H. Van Anda, A. Volonterio

Molecules dissolved in liquids attract and are constantly surrounded by solvent molecules. These attractive forces between the solute and the solvent cause a dissolution to form in the first place. A shell of the solvent molecules is temporarily held around the solute, whereas other solvent molecules are free to move about in the liquid. Creation and maintenance of such a shell are short-lived, typically a nanosecond. Restricting the solvent's motion is energetically costly; the solvents have reduced freedom while they are held in the organized shell.

We have created shells called capsules that are fixed solvent molecules bound together permanently. In capsules the energetic penalty has already been paid during synthesis, and they provide a welcome environment for molecules that fill the space. We have made cylindrical capsules that can be adjusted in length by incorporating small spacer elements. Long, thin molecules such as normal alkanes fit inside these structures, and they do so because they liberate the solvent shell when they go inside. Figure 1 shows another narrow molecule, anandamide, inside a capsule that has 2 layers of spacers around its center. Anandamide is the endogenous ligand for the cannabinoid receptors, and this capsular arrangement isolates this ligand. The ligand can be released under the control of acids and bases. The use of these capsules for drug transport, drug targeting, and drug delivery is being explored.

Fig. 1. A cylindrical capsule with 2 belts of spacer elements is held together by hydrogen bonds (dotted lines). The space-filling model inside is of anandamide, the ligand for the cannabinoid receptor.

Another consequence of a fixed solvent shell is that it provides a straightjacket for molecules held inside. Ordinarily, molecules rotate rapidly around their internal bonds, and this movement allows them to take on a number of different shapes. The molecules can be in fully extended shapes or bent and even folded over in free solution. Within the cylindrical capsule, these motions are limited. We found that the amide in Figure 2 is held rigidly in the conformation (shape) shown. The alternative conformation would cause steric clashes between the fixed cylinder shell and the molecule inside and is prevented.

Fig. 2. Two conformations, Z and E, exist in equal amounts in solution for the tertiary amide (left). Only one of these can be accommodated in a cylindrical capsule (cartoons, right).

Many cellular processes as well as diseases involve a cascade of signals that is transmitted by proteins contacting other proteins. It would be desirable to interfere with such interactions and modulate the formation of these protein-protein complexes. Protein-protein interfaces tend to be large, featureless areas, and small molecules do not have enough surface to compete with other proteins. In some special instances, 1 of the 2 protein partners provides a deep groove in which small synthetic molecules can be useful as medicinal agents. Accordingly, we have been synthesizing molecular scaffolds that fill these deep groove structures. Figure 3 shows the scaffolds in which the positions shown as R present side chains in the approximate orientation and distances in which they are found in protein secondary structures such as α-helices. These synthetic structures can affect the protein signaling cascade in breast cancer.

Fig. 3. Rigid scaffold mimicking the i, i+4, and i+7 positions of a generic α-helix (left) and some representative peptidomimetic scaffolds (right).

We have also been concerned with the behavior of oily (lipidlike) molecules in aqueous solutions. A natural vessel that allows the dissolution of such oily molecules in water is a cavitand in which the exterior is hydrophilic but the interior is lipophilic. Figure 4 shows the arrangement of a oily molecule inside one of these structures. The cavitands fold and unfold for uptake and release of oily molecules much as do the cavitands' larger counterparts, the fatty acid–binding proteins that exist in biological systems.

Fig. 4. A water-soluble cavitand unfolds to allow a guest bound in its hydrophobic pocket to escape as another guest enters.

Publications

Ajami, D., Rebek, J., Jr. Adaptations of guest and host in expanded self-assembled capsules. Proc. Natl. Acad. Sci. U. S. A. 204:16000, 2007.

Biros, S.M., Moisan, L., Mann, E., Carella, A., Zhai, D., Reed, J.C., Rebek, J., Jr. Heterocyclic α-helix mimetics for targeting protein-protein interactions. Bioorg. Med. Chem. Lett. 17:4641, 2007.

Biros, S.M., Rebek, J., Jr. Structure and binding properties of water-soluble cavitands and capsules. Chem. Soc. Rev. 36:93, 2007.

Evan-Salem, T., Baruch, I., Avram, L., Cohen, Y., Palmer, L.C., Rebek, J., Jr. Resorcinarenes are hexameric capsules in solution. Proc. Natl. Acad. Sci. U. S. A. 103:12296, 2006.

Hooley, R.J., Rebek, J., Jr. A deep cavitand catalyzes the Diels-Alder reaction of bound maleimides. Org. Biomol. Chem. 5:3631, 2007.

Hooley, R.J., Van Anda, H.J., Rebek, J., Jr. Extraction of hydrophobic species into a water-soluble synthetic receptor. J. Am. Chem. Soc. 129:13464, 2007.

Moisan, L., Dale, T.J., Gombosuren, N., Biros, S.M., Mann, E., Hou, J.-L., Crisostomo, F.P., Rebek, J., Jr. Facile synthesis of pyridazine-based α-helix mimetics. Heterocycles 73:661, 2007.

Rebek, J., Jr. Contortions of encapsulated alkyl groups. Chem. Commun. (Camb.) 2777, 2007, Issue 27.

Salvio, R., Moisan, L., Ajami, D., Rebek, J., Jr. Tertiary amide rotation in a nanoscale host. Eur. J. Org. Chem. 16:2722, 2007.

Sánchez, L., Sierra, M., Martìn, N., Myles, A.J., Dale, T.J., Rebek, J., Jr., Seitz, W., Guldi, D.M. Exceptionally strong electronic communication through hydrogen bonds in porphyrin-C₆₀ pairs. Angew. Chem. Int. Ed. 45:4637, 2006.

Van Anda, H., Myles, A.J., Rebek, J., Jr. Charge-transfer and encapsulation in a synthetic, self-assembled receptor. N. J. Chem. 31:631, 2007.

Volonterio, A., Moisan, L., Rebek, J., Jr. Synthesis of pyridazine-based scaffolds as α-helix mimetics. Org. Lett. 9:3733, 2007.