Combinatorial chemistry encoded libraries

Maclean, D. Schullek,J. R. Murphy,M. M. Ni,Z-J. Gordon,E. R. Gallop, M. A. Encoded Combinatorial Chemistry Synthesis and Screening of a Library of Highly Functionalized Pyrrolidines, Proc. Natl. Acad. Sci. USA... 

Xiao, X.-Y. Parandoosh, Z. Nova, M. P. Design and Synthesis of aTaxoid Library Using Radiofrequency Encoded Combinatorial Chemistry, J. Org. Chem. 1997, 62, 6029. 

Nestler, H. P Bartlett, P. A., Still, W. C. A General Method for Molecular Tagging of Encoded Combinatorial Chemistry Libraries. J. Org. Chem. 1994, 59, 4723-4724. 

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. 

Battersby BJ, Bryant D, Meutermans W, Matthews D, Smythe ML, Trau M, Toward larger chemical libraries encoding with fluorescent colloids in combinatorial chemistry, J. Am. Chem. Soc., 122 2138-2139, 2000. 

This review will cover encoding techniques for small organic molecule pool libraries, one of the most challenging and powerful techniques in combinatorial chemistry. A short introduction to illustrate briefly the advantages in library encoding and to compare the method with other structure determination techniques will be given, but for a more detailed introduction the reader should look elsewhere in this book [1]. 

Yamashita and Weinstock [62], Scott et al. [63, 64] and Egner et al. [65] reported the use of fluorophores in combinatorial chemistry and, in particular, as tags for pool library encoding. Multiple fluorophores were pre-encoded at a very low loading level (>0.1%) and the codes were read via various fluorimetric detection techniques [63]. Small tripeptide libraries were tested and decoded with success [62], but many potential drawbacks were also highlighted [63] so that a careful assessment of all the relevant variables (solid support... 

While considerable efforts have been spent in the past few years in the field of solid supports for combinatorial chemistry [73], most of them were devoted to modified polystyrenic beads with different sizes, loadings or swelling properties [74], or carrying different functionalities or linkers for library synthesis [75], or to solid supports different from resin beads (pins [76], cellulose [77], soluble supports [78], and so on). Few reports dealt with labelled solid supports prepared by chemical reactions (see the previous paragraphs) and significant efforts in the field of material sciences to obtain intrinsically labeled, nonchemically encoded, easily readable, combinatorial solid supports have not been reported. 

Nestler HP, Bartlett PA, Still WC, A general method for molecular tagging of encoded combinatorial chemistry libraries, J. Org. Chem., 59 4723 4724, 1994. 

Maclean D, Schullek JR, Murphy MM, Ni ZJ, Gordon EM, Gallop MA, Encoded combinatorial chemistry synthesis and screening of a library of highly functionalized pyrrolidines, Proc. Natl. Acad. Sci. USA, 94 2805-2810, 1997. 

Hochlowski JE, Whittern DN, Sowin TJ, Encoding of combinatorial chemistry libraries by fluorine-19 NMR. J. Comb. Chem., 1 291-293, 1999. 

Xiao X, Parandoosh Z, Nova MP, Design and synthesis of a taxoid library using radiofrequency encoded combinatorial chemistry, J. Org. Chem. 62 6029-6033, 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. 

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