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Anion Recognition

Our success in improving the cation affinity of the cyclopeptides by conformational control motivated us to use a similar approach to increase anion affinity also. Considering that 70-75% of all enzyme substrates and cofactors are negatively charged, the efficient and selective molecular recognition of anions is probably even more important in Nature than that of cations [19]. The most important biologically relevant anions are phosphate (inorganic or in the form of esters such as DNA, RNA, ATP, etc.), sulfate, carboxylate, and chloride. In anion complexation by natural systems two basic types of interaction can be distinguished - electrostatic interaction and hydrogen-bond formation, with the latter usually inducing higher binding selectivity because of the directionality of hydrogen bonds. An important binding motif for anions that occurs, for example, in the phosphate binding protein (PBP) and carboxypeptidase A, namely the interaction between an anion and the protonated guanidinium group of an arginine side-chain, makes use of a combination of both effects (for more on this ion pair interaction see Chapter 2.3). Other peptides, such as the sulfate binding protein (SBP) require no strong electrostatic interactions for anion recognition, and the main contribution to substrate binding comes from a defined array of hydrogen bonds inside the active center between the anion and NH groups of the protein backbone, serine OH, or tryptophan NH groups [19].

Although Nature demonstrates that proteins efficiently bind anions in aqueous solution, differences between the properties of cations and anions make complex-ation of the latter generally more difficult. Anions are, for example, usually larger than cations and therefore need a larger cavity for complexation. In addition, the hydration energy of most anions is higher than that of cations. Therefore, anion receptors have to compete more efficiently with solvent molecules. Moreover, many anions are involved in protonation equilibria, making it necessary for receptors to be active in an appropriate pH window. Finally, anions occur in a range of geometries such as spherical (halides), linear (N3_), planar (NO3_), tetrahedral (SO42~), or octahedral (PF6_), which requires more elaborate receptor design.

These problems were the reason why the development of artificial anion receptors took considerably longer than that of cation receptors. Today, however, many systems exist with which the difficulties of anion complexation can be overcome [20]. With the exception of receptors that bind anions by coordinative interactions (Lewis acid ■■■ anion), most systems make use of the same basic principles of anion complexation also found in Nature, namely electrostatic interactions and hydrogen-bond formation. Guanidinium-based receptors, for example, mimic the anion recognition in PBP or carboxypeptidase A (see Chapter 2.3), whereas neutral urea- or amide-based receptors mimic that of SBP. Although anion binding relies solely on hydrogen-bond formation in the latter example, some neutral anion receptors have high anion affinity even in polar solvents such as acetonitrile or DMSO [21]. Because of the high hydration energies of anions, however, complex formation in water often proved to be weak if present at all (cf also Box 7).

In the course of our investigations on the interactions of cyclopeptides such as 2 or 3 with cations we also encountered the anion binding capacity of these compounds. For 3, we showed, for example, that to enable optimum interactions with anions, the peptide adopts a conformation with all NH groups pointing into the cavity center [13], and by stabilizing a peptide conformation with diverging NH groups we could completely eliminate this anion binding capacity [18]. We were therefore curious to discover whether the reversed effect could also be achieved, i.e. an increase in anion affinity by stabilization of a peptide conformation with converging NH groups.

Our approach to induce such a conformation is based on the orienting effects of pyridyl ring nitrogens on adjacent NH bonds, and consisted in replacement of the 3-aminobenzoic acids in the cyclopeptide ring of 3 by 6-aminopicolinic acid sub-units [22]. NH bonds usually adopt a parallel orientation to the lone pair of the ring nitrogen, because of the antiparallel arrangement of the corresponding dipole

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