Scientific Report 2006

The Skaggs Institute for Chemical Biology

Convex and Concave Recognition Surfaces

J. Rebek, Jr., D. Ajami, E. Barrett, S. Biros, S. Butterfield, A. Carella, T.J. Dale, N. Gombosuren, C. Haas, R.J. Hooley, T. Iwasawa, E. Mann, L. Moisan, A. Myles, B. Purse, R. Salvio, M. Schramm, H. Van Anda, A. Volonterio, F. Zelder

Mimetics of α-Helices

Protein-protein interactions are involved in the regulation of a wide variety of biological processes. These recognition events often occur between a large protein containing a well-defined binding site and a smaller protein with features complementary to the site. This relationship has been compared with that of a lock and its key: only a key with the correct grooves and notches will fit and elicit a response. Regulation of these events by small, synthetic molecules is a challenging but desirable goal in medicinal chemistry. Structures that can selectively enhance or antagonize protein-protein interactions have much promise as pharmaceuticals.

We have constructed a series of molecules that target protein-protein interactions in which the smaller protein adopts an α-helical conformation (Fig. 1). The synthesis of these molecules is modular and readily amenable to combinatorial techniques. These structures act as scaffolds to project functional groups (the “grooves” and “notches”) in a manner that closely resembles that of an α-helical protein. We have built small libraries of these compounds that target a number of protein-protein interactions implicated in, for example, prolonged cancer states, chronic neuropathic pain, and epilepsy.

Fig. 1. Left, Line structure and skeletal model of a synthetic, scaffold-based α-helix mimetic. Right, Overlay of the scaffold (light gray) with an α-helical peptide (black tube); the side-chain functional groups used to recognize other proteins are shown as spheres.

Cavitands as Receptors

Cavitands are concave hosts that bind small molecules of complementary size, shape, and chemical surface. Deepened cavitands enclose most of a small guest, but the open end reduces the selectivity and exposes part of the guest to the external medium. Exquisite selectivities can be achieved by using capsules that completely surround the guest. We recently prepared a water-soluble cavitand (Fig. 2) that coaxes hydrophobic guests into the cavity, where they are more or less shielded from the aqueous environment. These complexes are kinetically stable; that is, exchange of guests is slow on the nuclear magnetic resonance timescale. The guests are surrounded by surfaces made of aromatic subunits, allowing van der Waals interactions between host and guest. This attraction leads to conformational changes for normal hydrocarbons such as octane; the hydrocarbons coil to make better contacts with the inner lining of the receptor and reduce the surfaces exposed to the aqueous environment.

Fig. 2. A water-soluble synthetic receptor extracts normal alkanes and other insoluble species into aqueous solution. Inside the cavity, the alkanes coil into a helix to maximize hydrophobic contacts with the receptor and tumble rapidly on the nuclear magnetic resonance timescale.

A cavitand with doors that can be rotated over the open end has been synthesized and characterized. The doors shield guests from water and limit the size of guests that fit the space. The increase in selectivity for small guests allows cycloalkanes inside but excludes longer linear counterparts of cycloalkanes. Cyclopentane inside the cavitand is shown in Figure 3. The binding of n-hexane causes the doors to fully open and expose the guest to the aqueous surroundings. The closed doors also reduce the rate of motion as various small guests go in and out of the cavitand.

Fig. 3. Two views of a water-soluble cavitand with rotating doors on its upper rim. Two doors close access to the cavity and slow the uptake and release of guests. The guest shown is cyclopentane.

Cavitands have also been outfitted for catalysis by introducing a metal complex fused to the upper rim. This complex features a deep cavity for driving guest recognition and a metal ion at the top of the cavity that is positioned to coordinate a phosphate group of the guest. These binding forces act simultaneously on smaller molecules that bear phosphocholine subunits as shown in Figure 4. Reactions that have been catalyzed involving a choline substrate include acylation, aminolysis, and ester cleavage.

Fig. 4. Left, Line drawing of a cavitand outfitted with a salen ligand with a zinc ion. Right, Energy-minimized structure of the complex of the cavitand and a simplified phosphocholine model (a wall of the cavitand has been removed for viewing clarity).

Publications

Haas, C.H., Biros, S.M., Rebek, J., Jr. Binding properties of cavitands in aqueous solution: the influence of charge on guest selectivity. Chem. Commun. (Camb.) 6044, 2005, Issue 48.

Hooley, R.J., Biros, S.M., Rebek, J., Jr. A deep, water-soluble cavitand acts as a phase-transfer catalyst for hydrophobic species. Angew. Chem. Int. Ed. 45:3517, 2006.

Hooley, R.J., Biros, S.M., Rebek, J., Jr. Normal hydrocarbons writhe and tumble rapidly in a deep, water-soluble cavitand. Chem. Commun. (Camb.) 509, 2006, Issue 5.

Hooley, R.J., Rebek, J., Jr. Deep cavitands provide organized solvation of reactions. J. Am. Chem. Soc. 27:11904, 2005.

Hooley, R.J., Van Anda, H.J., Rebek, J., Jr. Cavitands with revolving doors regulate binding selectivities and rates in water. J. Am. Chem. Soc. 128:3894, 2006.

Menozzi, E., Onagi, H., Rheingold, A.L., Rebek, J., Jr. Extended cavitands of nanoscale dimensions. Eur. J. Org. Chem. 3633, 2005, Issue 17.

Menozzi, E., Rebek, J., Jr. Metal directed assembly of ditopic containers and their complexes with alkylammonium salts. Chem. Commun. (Camb.) 5530, 2005, Issue 44.

Purse, B.W., Gissot, A., Rebek, J., Jr. A deep cavitand provides a structured environment for the Menschutkin reaction. J. Am. Chem. Soc. 127:11222, 2005.

Purse, B.W., Rebek, J., Jr. Functional cavitands: chemical reactivity in structured environments. Proc. Natl. Acad. Sci. U. S. A. 102:10777, 2005.

Zelder, F.H., Rebek, J., Jr. Cavitand templated catalysis of acetylcholine. Chem. Commun. (Camb.) 753, 2006, Issue 7.

Zelder, F.H., Salvio, R., Rebek, J., Jr. A synthetic receptor for phosphocholine esters. Chem. Commun. (Camb.) 1280, 2006, Issue 12.