Combinatorial chemistry deconvolution

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Much of the early work in combinatorial chemistry focused on the preparation of large mixtures of compounds. The most widely used technique for mixture synthesis is the split/recombine method which assures that each component of the mixture is present in approximately equimolar concentrations. The structures of the bound ligands are determined either through an iterative, or reclusive, deconvolution strategy or through the use of encoded libraries. 

Seneci P, Direct deconvolution techniques for pool libraries of small organic molecules, Combinatorial Chemistry and Combinatorial Technologies Methods and Applications (Eds. Miertus S, Fassina G), 153-192, 2005, Chapter 8, this volume. 

Baldwin JJ, Dolle R, Deconvolution tools for solid-phase synthesis, A Practical Guide to Combinatorial Chemistry, (Eds. Czarnik AW, DeWitt SH), ACS, Washington, 153-174, 1997. 

In the synthesis of combinatorial libraries, there is a raft of tactical issues that need to be tackled. Will the library be made of mixtures or discrete compounds Prepared by solid-phase or solution-phase Screened in solution or attached to beads What level of purification and characterization is needed Will hits be identified by deconvolution, encoding techniques, or other means These are aU crucial operational aspects of combinatorial chemistry but it is equally important not to concentrate on them to the extent of missing the big picture. At the end of the day, neither a biological assay nor a medicinal chemist care how a compound was made. It is vital, though, that the tactical decisions do not prevent one from making the right compounds. Combinatorial synthesis is a means to an end, not an end in itself. 

Combinatorial Chemistry. The application of high-throughput, parallel methods to the synthesis, analysis, screening, and testing of materials. This approach relies on robotics and computer-assisted methods to generate and analyze the results. Synthesis, analysis, and testing of samples occurs in the wells of microtiter plates, which may contain as few as 96 samples or as many as a few thousand. Solid-phase and solution methods are used, and samples may be one-bead-one-com-pound" or they may contain mixtures, which require "deconvolution" to determine which component is responsible for observed activity. 

I can only quote Pierre Potier, who is also a natural products chemist, who said about combinatorial chemistry that it is what God did too. The natural products in living organisms are just the products of combinatorial chemistry. As for myself, though, I have never been tempted to go into it. The real intellectual challenge is in the deconvolution of the mixture and in the identification of its components. 

TABLE 2-12 Simplified Deconvolution Scheme for a 20-Compound Combinatorial Chemistry Saeen... 

Combidex. 5ir Feruiimxiraii Combinatorial chemistry. 26-27. 43-63 analytical techniques in. 51-.52 bogus-coin detection in. 50 carbohydrates in. 47. 47f chromatography in. 51 cleavage reactions in. 49. 61 deconvolution in. 26. 27t. 61 development uf. 43... 

Figure 3.1. A comparison of (a) traditional chemistry with three approaches to combinatorial chemistry (b) array synthesis directly identifies an active compound (c) one-pot simultaneous synthesis necessitates deconvolution and (d) indexed library indirectly indicates active compounds.

JJ Baldwin, RE Dolle. Deconvolution methods in solid-phase synthesis. In WH Moos, MR Pavia, BK Kay, AD Ellington, eds. Annual Reports in Combinatorial Chemistry and Molecular Diversity. Leiden ESCOM, 1997, pp. 287-297. 

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