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Beyond Kinetics

A surprising receptor emerges from a dynamic combinatorial library

by A. Maureen Rouhi
May 2, 2005 | A version of this story appeared in Volume 83, Issue 18


In work that demonstrates the power of dynamic combinatorial libraries--and the realm beyond kinetic control of synthesis--researchers have isolated a structure resembling two linked doughnuts that is a potent receptor for acetylcholine.

Credit: © SCIENCE 2005
Credit: © SCIENCE 2005

Working from a 44-day-old brew of the neurotransmitter and simple pseudopeptides, Jeremy K. M. Sanders and coworkers at the University of Cambridge obtained a 67% yield of an elaborate, diastereomerically pure [2]catenane consisting of two interlocked macrocylic trimers having submicromolar affinity for acetylcholine (Science 2005, 308, 667).

"In a single-step, one-pot process on a preparative scale, we have generated an unpredictable and exquisitely complicated" receptor, Sanders tells C&EN. "Nobody would have thought to design this structure, and yet it has evolved in response to the presence of acetylcholine."

Dynamic combinatorial libraries, Sanders explains, are assembled from simple building blocks that are joined reversibly (C&EN, Sept. 2, 2002, page 31). Because of the reversibility, a library left long enough to equilibrate yields a product distribution that reflects the most thermodynamically favored members. The presence of a template, such as acetylcholine in the present work, forces the system to select and amplify members that are most complementary to--that are receptors of--the template.

That a system of such simple units interacting under mild conditions could evolve into an intricate form that is not readily accessible otherwise is a significant achievement by itself, suggests J. Fraser Stoddart of the University of California, Los Angeles, who is one of the leading practitioners of dynamic chemistry. Yet its implications on the practice of synthesis are profound, he adds.

In synthetic chemistry, "there is a game beyond kinetic control," Stoddart says. The new work from Sanders demonstrates that "what meets the eye immediately is only a glimpse of what's on the palette. You need patience, you need to wait around to let this whole library--the canvas--unfold all its glory." Kinetically controlled events have dominated the practice of synthesis, whereas allowing thermodynamic control to reign could yield more interesting structures under much milder conditions, he suggests.

Notwithstanding the aesthetic appeal of the acetylcholine receptor that emerged from the work, "we don't have a specific use for it," Sanders admits. "It is just much better than any synthetic acetylcholine receptor that has been carefully designed."



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