X

Fig. 2.3.6. Structure, derived from molecular modeling, of 2 with N-acetylphenylalanine in water (intermolecular hydrogen bonds are shown as broken lines).

necessary to achieve substrate selectivity. Additional interactions between the substrate and the receptor are therefore needed to make the recognition process selective. Surprisingly, this is already true in the simple guanidiniocarbonyl pyrroles presented so far. The binding strength for complexation of different N-acetyl amino acid carboxylates by the ethylamide-substituted receptor 2 in aqueous dimethyl sulfoxide depends significantly on the type of amino acid [13]. The association constant for the binding of d/L-phenylalanine (K = 1700 m-1) is more than twice as strong as for d/L-alanine (K = 770 m-1); whereas the association constant for d/L-lysine (K = 360 m-1) is approximately half as strong. The differences in complex stability among the various amino acids must result from secondary interactions of their side-chains with the receptor. For phenylalanine the aromatic ring probably re-stacks with the acyl guanidinium unit of 2, at least according to molecular modeling studies. This cation-re interaction [14] further stabilizes the complex (Figure 2.3.6). In contrast with this, the positively charged w-ammonium group in lysine reduces the binding affinity relative to alanine, because of unfavorable electrostatic interactions with the positively charged guanidinium group.

The chiral, L-valine derived receptor 6 not only had side-chain selectivity but also moderate stereoselectivity [10]. For example, for alanine the l enantiomer is bound by a factor of three better than the d enantiomer. Because experimental structural information was not available, molecular modeling was used to help rationalize the observed binding selectivity. In the complex with the l enantiomer the binding constant (K = 1610 mol-1) is larger than for binding by the ethylamide receptor 2 (K = 770 mol-1), probably because of an additional hydrogen bond from the terminal carbamoyl group. This is also indicated by a corresponding complexation-induced shift change of this proton in the NMR. With D-alanine there is an unfavorable steric repulsion between the methyl group of the amino acid and the isopropyl side-chain of the receptor which is not present in the complex with the l enantiomer, in which the methyl group points away from the isopropyl group.

same recognition motif as in 2

same recognition motif as in 2

Fig. 2.3.7. An unfavorable steric interaction between the two side-chains in the complex between d-alanine and receptor 6 reduces the binding affinity.

Because the H-bond from the terminal carbamoyl group to the carboxylate is not strong enough to compensate for this increased steric strain, this H-bond is most probably lost in the complex with D-alanine (Figure 2.3.7). The remaining binding motif therefore resembles the simple amide-substituted guanidiniocarbonyl pyrrole 2, which lacks the sterically demanding isopropyl group. In accordance with this, the binding constant for the D enantiomer is also approximately the same (K = 730 moH).

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