Encoding of chemical compounds as described above is based on the difficulties of determining the structure of each library member individually by analytical methods. For most organic compounds, this would require one- or multi-dimensional NMR techniques that are not suitable for large numbers. Moreover, analysis would also require a sufficient amount of material. An alternative approach is based on the preparation of the product simultaneously with the synthesis of a tagging compound that can be analyzed more easily than the original product. This approach was first discussed on the basis of oligonucleotides as chemical tags in which individual nucleotides serve as increments of the tag [7,8]. Analogously, peptides have been used as chemical tags [9-11]. Both biopolymers are decoded by sequencing, and the sequence is related to the structure of the product. A limitation of these coding strategies is the possibility that not only the product but also the tag displays some biological activity, and thus can cause false-positive screening hits. Another limiting factor is the orthogonality of the tagging method and the chemical reaction conditions used to prepare the library. A solution to this latter problem however was described recently: a library of hexapeptides was chemically tagged using polyhalogenated phenoxyalkyl derivatives which were covalently attached to the polystyrene backbone [12,13]. The analysis/decoding of these tags was performed after cleavage from the support by electron capture gas chromatography. However, the problem of chemical orthogonality and different cleavage conditions may cause problems.
A related approach uses mono-amides of iminodiacetic acid as molecular tags . The tags are attached to the support via the free carboxylic acid group and a free amino group bound to the support. The imino nitrogen group of the first part of the codon serves as attachment point for the carboxylic acid group of the next iminodiacetic acid mono amide. Due to the amide structure, the tags are chemically inert. Cleavage and conversion to the corresponding dansyl derivatives allow their characterization by HPLC and fluorimetry.
All chemical tagging strategies are greatly limited by the additional synthetic transformations required to build up not only the product but also the tag. Consequently, this encoding method is only used exceptionally for the production of libraries [15-17].
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