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.
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.
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.
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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.