Amplification of acetylcholine-binding catenanes from dynamic combinatorial libraries

Directed chemical synthesis can produce a vast range of molecular structures, but the intended product must be known at the outset. In contrast, evolution in nature can lead to efficient receptors and catalysts whose structures defy prediction. To access such unpredictable structures, researchers have prepared dynamic combinatorial libraries, in which reversibly-binding building blocks assemble around a receptor target. They selected for an acetylcholine receptor by adding the neurotransmitter to chloroform/dimethylsulfoxide solutions of dipeptide hydrazones [proline-phenylalanine or proline-(cyclohexyl)alanine], which reversibly combine through hydrazone linkages. At thermodynamic equilibrium, the dominant receptor structure was an elaborate [2]-catenane, consisting of two interlocked macrocyclic trimers. This complex receptor with a 100 nanomolar affinity for acetylcholine could be isolated on a preparative scale in 65% yield.

March 29, 2005

Original web page at Science