Cation Recognition

Important cation binding systems in Nature are, for example, a class of macro-cyclic compounds termed ionophores and proteins that bind quaternary ammonium ions such as acetylcholine. The ionophores valinomycin 1, nonactin, the ennia-tines, and baeuvericin are cation binders that are structurally quite diverse, yet

their mode of action is closely related [1]. All ionophores transport cations through biological membranes and thus cause a perturbation of the trans-membrane ionic balance. As a consequence, valinomycin and nonactin, for example, have high antibacterial activity (Figure 2.2.1).

Valinomycin is a cyclic depsipeptide containing a subunit sequence of L-valine, D-hydroxyisovaleric acid, D-valine, and L-lactic acid that is repeated three times in the ring. This structure enables 1 to adopt a conformation in which the six car-bonyl groups of the valine residues are almost perfectly preorganized for the com-plexation of a K+ ion. In the complex formed the isopropyl groups around the valinomycin ring all point outward, rendering the whole aggregate lipophilic, a property that accounts for the ability of 1 to transport potassium through a membrane. A cyclic arrangement of oxygen atoms is a common structural motif of all ionophores, and the cation affinity of these compounds therefore has a similar explanation.

Incidentally, C. J. Pedersen's first report on crown ethers and their complexes was published in the same year as the mechanism of the biological activity of vali-nomycin was clarified [2]. Crown ethers are cyclic derivatives of polyethylene glycol of varying ring size, an example of which is also depicted in Figure 2.2.1. The structural relationship with the ionophores is clearly visible. It is thus not surprising that crown ethers also bind metal cations by coordination with the oxygen atoms [1, 3].

Coordination by oxygen atoms is not the only mechanism with which cations can be bound in the cavity of a natural or non-natural receptor, however. The crystal structure of acetylcholinesterase, an enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine into choline and acetate, with the inhibitor deca-methonium (Me3N+(CH2)10NMe3+) included inside the active center showed an unexpected large number of aromatic amino acid side-chains in the vicinity of the cationic headgroups of the substrate [4]. The binding site responsible for the com-plexation of the quaternary ammonium group of acetylcholine is lined by 14 aromatic residues, for example, of which one tryptophan indole ring is in close contact with the bound cation. Similar contacts between aromatic groups and cations are quite common in natural cation-binding proteins, and they also contribute to the non-covalent stabilization of protein conformations [5]. This type of interaction has been termed cation-re interaction [6]. It is also responsible for the cation affinity of artificial cation receptors such as, for example, the calixarenes [7].

Calixarenes are formed by condensation of a p-substituted phenol with formaldehyde [8]. These macrocycles are conformationally quite flexible but, by introducing suitable substituents in the aromatic subunits, the so-called cone conformation, in which all aromatic subunits point into the same direction, can be stabilized. This conformation is usually best suited to complex guest molecules because it has a well defined hydrophobic cavity. An inclusion of cations such as ammonium ions or quaternary ammonium ions into this cavity can be demonstrated, for example, by the characteristic upfield shifts of guest signals in the NMR, an effect that is a consequence of the close proximity of the corresponding protons to the surfaces of the aromatic receptor subunits in the complex.

Calixarenes provided the main inspiration for the artificial receptors studied in my group. We wanted to develop a new class of macrocyclic host with binding properties and structural variability similar to calixarenes but a closer relationship to natural systems. The obvious choice was, of course, to base such receptors on cyclopeptides, macrocyclic compounds that are composed of the same subunits as the natural systems.

When we started our investigations, there were surprisingly few reports on the use of macrocyclic peptides as artificial receptors [9], most probably because cyclo-peptides, especially larger ones, have a tendency to adopt conformations in solution unsuitable for inclusion of a guest molecule [10]. Moreover, prediction of the preferred solution conformations of such peptides is still difficult. These disadvantages can be overcome to some extent, however, by incorporating rigid amino acid subunits in the ring [11]. This strategy usually enables control of the conforma-tional behavior of a cyclopeptide, and it should therefore also be suitable for stabilization of peptide conformations that have well defined cavities. In this respect we expected peptides containing 3-aminobenzoic acid as conformational constraint to have particularly interesting receptor properties. As Figure 2.2.2 illustrates, introduction of such aromatic subunits in every other position of a cyclopeptide ring affords structures that can be regarded as hybrids between conventional cyclo-peptides and calixarenes. If these compounds adopt conformations in solution similar to those of calixarenes, one can also expect similar binding properties. The aromatic subunits of the cyclopeptides could, for example, induce cation affinity by means of cation-re interactions.

The starting point of our investigations was a cyclic hexapeptide containing 3-aminobenzoic acid and glutamic acid-5-isopropyl ester subunits 2 [12]. Our structural assignment showed that this cyclopeptide preferentially adopts conformations

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