Encoded combinatorial synthesis

Identification of active library components is done by micro sequencing (peptide libraries) or by incorporation and recognition of the tag associated with each bead (nonpeptide libraries). An example of this latter approach, known as encoded combinatorial synthesis [19], may use the dialkylamine tagging system shown in Fig. 7. The amine group of the tag addition site is acylated with iminodi-acetic anhydride to yield a pentafluorophenyl ester derivative. The active ester is reacted with a binary mixture of secondary alkylamines, leading to a tag polymer. 

Fig. 13.2. Use of chemical tags to encode the sequence in a combinatorial synthesis on a solid support. Reproduced from W. C. Still, Acc. Chem. Res., 29, 155 (1996), by permission of the American Chemical Society.

Scheme 13.57. Use of Chemical Tags to Encode Sequence in Combinatorial Synthesis on Solid...

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. 

Figure 6.11 The use of oligonucleotides to encode a peptide combinatorial synthesis for a library based on two building blocks...

Outline the range of encoding methods used to deduce the structures of compounds produced in a Furka mix and split combinatorial synthesis. 

Baldwin JJ, Henderson I, Recent advances in the generation of small-molecule combinatorial libraries encoded split synthesis and solid-phase synthetic methodology, Med. Res. Rev., 16 391-405, 1996. 

Armstrong RW, Brown SD, Keating TA, Tempest PA, Combinatorial synthesis exploiting multiple-component condensations, microchip encoding and resin capture, in Combinatorial Chemistry Synthesis and Application (Eds. Wilson SR, Czarnik AW), pp. 153-190, 1997, John Wiley Sons, New York. 

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. 

Lane SJ, Pipe A, Unambiguous bead decoding by microelectrospray capillary electrochromatography tandem mass spectrometry of dansylated secondary amine tags from encoded combinatorial organic synthesis, Rapid Common. Mass Spectrom., 12 667-674, 1998. 

Scott RH, Barnes C, Gerhard U, Balasubramanian S, Exploring a chemical encoding strategy for combinatorial synthesis using Friedel-Crafts alkylation, Chem. Commun., pp. 1331-1332, 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. 

Armstrong RW, Tempest PA, Cargill JF, Microchip encoded combinatorial libraries, Generation of a spatially encoded library from a pool synthesis. Chimia, 50 258-260, 1996. 

Barnes C, Scott RH, Balasubramanian S, Progress in chemical encoding for combinatorial synthesis, Recent Res. Dev. Org. Chem., 2 367-379, 1998. 

One of the most powerful and systematic methods for the synthesis of an encoded combinatorial library is the so called split synthesis procedure (Fig. 2) [4]. 

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. 

Z Ni, D Maclean, CP Holmes, MM Murphy, B Ruhland, JW Jacobs, EM Gordon, MA Gallop. A versatile approach to encoding combinatorial organic synthesis using chemically robust secondary amine tags. J Med Chem 39 1601-1608, 1996. 

Ni, Z-J Maclean, D. Holmes, C.P. Murphy, M.M. Ruhland, B. Jacobs, J.W. Gordon, E.M. Gallop, M.A. Versatile Approach to Encoding Combinatorial Organic Synthesis Using Chemically Robust Secondary Amine Tags, J. Med. Chem. 39, 1601-1608 (1996). 

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