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Structural Studies on Hydrogen‐Bonding Receptors for Barbiturate Guests That Use Metal Ions as Allosteric Inhibitors
Author(s) -
AlSayah Mohammad H.,
McDonald Robert,
Branda Neil R.
Publication year - 2004
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300389
Subject(s) - chemistry , allosteric regulation , intramolecular force , hydrogen bond , barbiturate , stereochemistry , metal , metal ions in aqueous solution , receptor , molecule , organic chemistry , biochemistry , psychology , psychiatry
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 × 10 3 M −1 in 9:1 CD 2 Cl 2 /CD 3 CN) 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)