Structural Studies on Hydrogen‐Bonding Receptors for Barbiturate Guests That Use Metal Ions as Allosteric Inhibitors

Abstract

Receptor 1 was designed to bind barbiturate substrates through a six‐point hydrogen‐bonding motif only in the absence of metal allosteric cofactors. It was predicted that the binding of metal ions by bipyridine ligands in 1 would result in a geometric change in the receptor to inhibit substrate recognition. However, receptor 1 showed minimal affinity for the barbiturate guests even in the absence of the metal. Binding studies on model compounds 2, 3, 5, and 6 revealed that the inactivity of 1 is due to an intramolecular hydrogen bond between the N−H donor groups and the nitrogen atoms on the first heterocycle of the bipyridine ligands. This intramolecular hydrogen‐bonding was eliminated by altering the position of the tether between the bipyridine ligands and the active site to produce receptor 7. Consequently, the high affinity exhibited by 7 for the barbiturate substrate (K_a = 2.8±0.7 × 10³ M⁻¹ in 9:1 CD₂Cl₂/CD₃CN) was significantly reduced by the addition of Zn^II ions as a negative allosteric co‐factor. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)