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Implicit in the term discovery is the idea of seeing something new. Yet, chemists for generations have sought to discover new reac-tions using mechanism-based, hypothesis-driven experiments. Inherent in the ex-perimental design has been a hallmark ofinvention—the achievement of a molecularinterconversion that verifies the inventor’sintuition. Of course, serendipity hasenriched reaction discovery since the field’sinception. Can the invention of neworganic reactions be systematized in a for-mat that maximizes the opportunity fordiscovery? In a recent paper in Nature, Liuand coworkers have taken a major step inthis direction with an approach to reactionscreening that does not depend on any par-ticular property of the starting materials orproducts1. DNA hybridization provides thetemplate for chemical synthesis, and molec-ular biology tools are used to interpret theoutcomes of the screens.

In recent years, chemists have gainedspeed in their search for both new reactivityand optimization of existing importantreactions by embracing the principles ofhigh-throughput screening2. Some of theseefforts even resemble ‘selections’ that relyon optical signatures to signal the desiredchemical event within complex mixtures orarrays3,4. Along the way, the merging of dis-ciplines has contributed to the developmentof new processes for organic synthesis.New reactions are now found using cata-lysts that are inorganic coordination com-pounds, organometallic species, simpleorganic structures, enzymes or catalyticantibodies. Advances arise from all cornersof the periodic table and employ catalystsand molecular chaperones of both syntheticand biological origin across a staggeringmolecular-weight range.

With their approach, Liu and coworkershave taken reaction discovery in an entirelynew direction. And they have done it in away that tests and perhaps even helps toexpand the definition of ‘chemical biol-

ogy’5,6. Most journals and conferences onchemical biology focus on the use of chem-ical tools to probe important questions inbiology. In their recent paper, Liu andcoworkers instead use biological principlesto explore one essential activity of chem-istry—the discovery of previously un-known conversions of one substance toanother. They do so not by testing a specifichypothesis about a reaction mechanism,nor by examining a high-throughput screenof reaction parameters or catalysts for a sin-gle transformation. Rather, they systematizethe discovery process.

Using the tools of molecular biology andthe logic of DNA-templated organic syn-thesis, they created a multidimensionalreaction array system that allows for thesimultaneous evaluation of hundreds (andpotentially many thousands) of couplingreactions—those high-value processes inorganic synthesis that take functionalgroups A and B and unite them to producea new molecule C. Liu and colleaguesdemonstrate the power of their approach byidentifying known reactions and, moreimportantly, by discovering a new one.

In practice, the system begins with complementary strands of DNA attached to common functional groups, the basic structural elements of organic molecules(Fig. 1). Liu and coworkers set up two edgesof a functional group matrix with represen-tative DNA-coupled functionalities suchthat Watson-Crick base pairing elevates theeffective molarity of the various functionalgroups ‘A’ with the various functionalgroups ‘B’ in a pairwise fashion. This DNA-based organization of the functional groupsenables all A-B pairs to independently react(or not react) under a chosen set of reactionconditions.

Productive A+B reactions from the in vitromixture are then extracted using strepta-vidin-biotin affinity labeling. Because bond

formation between A and B causes thebiotin group on B to become covalentlylinked with A and its associated oligonu-cleotide, the DNA strands that are capturedby streptavidin-linked magnetic particlesencode the productive A-B combinations.Results are visualized by labeling the DNArepresenting all possible coupling combina-tions with a red fluorophore, whereas theDNA surviving the streptavidin bindingselection is labeled with a green fluoro-phore. When the mixture of red- and green-labeled DNA is analyzed on a DNAmicroarray, the location of the green spotsidentifies the reactive A-B pairs.

The initial demonstration of theapproach not only reveals a number of pre-viously known reactions under establishedreaction conditions, but moves beyondproof-of-principle experiments by expos-ing the A+B coupling matrix to a Pd(II) saltand revealing an unexpected coupling reac-tion between a double bond and a triplebond, which delivers a coupled product in the form of an enone. Following DNAmicroarray analysis, this new transforma-tion is validated under standard round-bottom flask conditions. As a result, a previ-ously unknown macrocyclization throughoxidative coupling between an alkyne andan alkene has been added to the syntheticchemist’s arsenal.

How many more unexpected transforma-tions lie in wait? It is tempting to suggestthat there are many. If so, the impact of thisapproach on synthetic chemistry could befar-reaching. New reactions advance thestate-of-the-art in synthesis in at least twocritical ways: they can streamline access tocomplex, high-value materials by enhan-cing efficiency7; no less significantly, theycan provide access to new chemical struc-tures (that is, ‘diversity space’) that are notcharacterized, let alone defined in terms offunction. One great appeal of the new discovery system is that it allows for pair-wise analysis of essentially any functionalgroup that can be covalently attached to a DNA strand. Bifunctional moieties (e.g., eneynes, diones) could also be intro-duced, setting the stage for the search for tandem, multistep reactions. Such complexity-generating reactions have been

1378 VOLUME 22 NUMBER 11 NOVEMBER 2004 NATURE BIOTECHNOLOGY

Scott J. Miller is in the Department ofChemistry, Boston College, 2609 Beacon Street,Chestnut Hill, Massachusetts 02467, USA.e-mail: scott.miller.1@bc.edu

DNA as a template for reaction discoveryScott J Miller

Biological tools enable researchers to discover new reactions from complex mixtures of different substrates.

Liu and coworkers use biologicalprinciples to discover previouslyunknown chemical conversions.

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treasured by complex-molecule chemists intheir pursuit of both targets8 and diversity-oriented syntheses9.

Are there any limitations to this app-roach? Perhaps yes, and primary amongthem is that the diversity of reaction con-ditions that can be explored may berestricted to those that are compatible withDNA, disulfide bonds and of course water.Significantly, these requirements corre-spond to reaction conditions that are ex-perimentally mild and environmentallybenign10. Novel functional-group inter-conversions that can be induced under mild conditions are enduring goals thateach generation of synthetic chemistsattempts to bring to the proverbial nextlevel. The technique of Liu and coworkers is

NATURE BIOTECHNOLOGY VOLUME 22 NUMBER 11 NOVEMBER 2004 1379

Codingregion for

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Select bond-forming combinations,amplify tag-DNA and hybridize

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Figure 1 Schematic representation of reaction discovery through DNA-templated synthesis, in vitroselection, and DNA microarray analysis. DNA-linked functional groups (blue and green) form pairwisecombinations through Watson-Crick base pairing. Those combinations that undergo a bond-formingchemical reaction pass an in vitro selection for binding to avidin and are identified by PCRamplification followed by DNA microarray analysis.

poised to make numerous contributions atthe practical level while at the same timepromising to accelerate discovery at theheart of chemistry through the identifica-tion of novel reactivities.

1. Kanan, M.W., Rozenman, M.M., Sakurai, K., Snyder,T.M. & Liu, D.R. Nature 431, 545–549 (2004).

2. Stambuli, J.P. & Hartwig, J.F. Curr. Opin. Chem. Biol.7, 420–426 (2003).

3. Reetz, M.T. Angew. Chem. Int. Ed. 40, 284–310(2001).

4. Evans, C.A. & Miller, S.J. Curr. Opin. Chem. Biol. 6,333–338 (2002).

5. Breslow, R. Acc. Chem. Res. 28, 146–153 (1995).6. Schultz, P.G. & Lerner, R.A. Nature 418, 485 (2002).7. Trost, B.M. Acc. Chem. Res. 35, 695–705 (2002).8. Nicoloau, K.C. Angew. Chem. Int. Ed. 39, 44–122

(2000).9. Schreiber, S.L. Science 287, 1964–1969 (2000).10. Anasta, P.T. & Kirchoff, M.M. Acc. Chem. Res. 35,

686–694 (2002).

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