August 14, 2008

Also appeared in print Aug. 18, 2008, p. 12

Enzyme Mimic

Amplifying Small Molecules

Supramolecular complex generates target compounds in PCR-like cascade reaction

Celia Henry Arnaud

Molecular amplification may now be just as feasible for small organic molecules as it has been for nucleic acids, according to a new study (J. Am. Chem. Soc., DOI: 10.1021/ja804076q). Such amplification, which improves analytical sensitivity, has until now been restricted to use of the polymerase chain reaction (PCR) on nucleic acids.

TARGET AMPLIFICATION When this supramolecular complex binds acetate (AcO), it opens to form a cavity that allows a pair of Zn(II)-salen ligands to catalyze an acyl transfer reaction between acetic anhydride and pyridyl carbinol, generating acetate that can activate even more catalyst.

"Name another type of system that can recognize a molecule, cause some sort of structural change, and then turn over a catalytic reaction that generates more of the molecule it recognized," says study leader Chad A. Mirkin, a chemistry professor at Northwestern University. "The bottom line is that when you move away from PCR, there are no other systems."

Mirkin and graduate student Hyo Jae Yoon achieved their PCR-inspired small-molecule detection system by using a supramolecular complex that recognizes acetate and catalyzes a reaction that generates more acetate. Mirkin previously used the same complex and reaction under acidic conditions to amplify the signal for small-molecule detection in a method analogous to enzyme-linked immunosorbent assays (C&EN, Jan. 24, 2005, page 9). In that technique, the complex recognized chloride and generated acetic acid.

The macrocyclic complex consists of two Zn(II)-salen groups connected on either side by rhodium(I)-thioether linkers that pin the complex down and keep the catalyst inactive. Under basic conditions, acetate displaces the thioethers, opening the complex and forming a cavity capable of catalyzing an acyl transfer reaction between pyridyl carbinol and acetic anhydride. The reaction is coupled to a fluorescent readout with a pH-sensitive dye. The catalyzed reaction generates more acetate, which in turn activates more catalyst in a cascade of reactions.

The method's applicability is limited only by "the creativity of a chemist trying to design a structure to recognize a molecule of interest," Mirkin says. Such molecules of interest could range from chemical weapons and biological toxins to neurotransmitters and small-molecule disease markers.

A key challenge in moving forward is extending the methodology from bimetallic to monometallic catalytic systems to expand the potential repertoire of catalytic reactions. Mirkin's group is building structures with pockets to protect the catalytic site, he says. "We can toggle back and forth between open and closed states, or inactive and catalytically active states, with a single metal as opposed to two metals." Such structures could also be used to introduce cocatalysts, he says.

"The strategy outlined in this paper can potentially be implemented for the production and detection of chemically or biologically important species," says Wenbin Lin, a chemistry professor at the University of North Carolina, Chapel Hill, who also studies enzyme-mimicking supramolecular complexes. "This work elegantly illustrates the great potential of metal-organic supramolecular systems in mimicking important biological processes."

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