Chemically Encoded Synthetic Libraries

Any chemically encoded library requires a double orthogonal chemical strategy, or the construction of elaborate tags/linkers on the solid support prior to the synthesis. Even when these are easily prepared and inert, the synthetic scheme becomes more complicated than direct deconvolution methods, where only the library synthesis is required. Sometimes the tag chemistry and the... 

Baldwin JJ, Design, synthesis and use of binary encoded synthetic chemical libraries, Molecular Diversity, 2 81-88, 1996. 

The primary library shown in Fig. 5.2, which was reported by Baldwin (1), was clearly designed as a source of biologically active molecules on several targets (why), thus compensating the efforts required for the chemical assessment and for a satisfactory characterization (when). The SP library was prepared in pools using chemical encoding (4, 5) to produce a population of around 62,000 individuals (how). The synthetic scheme was composed of both simple and more complex SP steps, and several monomer sets (A-F, Fig. 5.2) were used (what). These monomers were either commercially available or easily prepared from commercial precursors, while the library benzopyranic core was formed during the synthesis (how much). 

OBOC combinatorial bead-libraries can be considered as chemical microarrays that are spatially separable but non-addressable. The identity of the chemical compound on the positive beads can be determined directly with an automatic sequencer if it is an N-terminally unprotected peptide, by mass spectroscopy, or through chemical encoding. i A synthetic scheme for the OBOC library is shown in Figure 2. Using the highly efficient split-mix synthesis method,literally hundreds of thousands to millions of compounds can be prepared within a week. The recent... 

Tlie basic study of intermolecular interactions is facihtated by one-bead-one-stRicture libraries which can be powerful tools for the discovery of hgands to synthetic receptors and vice versa. Encoded combinatorial libraries have been useful for disclosing ligands for well-designed macrocyclic host molecules and to elucidate their specificities for peptide sequences. These studies led via receptors with more flexibility to simple host molecules without elaborate design that ai e accessible to combinatorial synthesis. One application is the development of chemical sensors for analytes that are otherwise difficult to detect or only non-specificaUy detected. Such hbraries have been used to find new catalysts and enzyme mimics. 

M. C, Jones, D.G., Tate, E.H., Heinkel, G.L., Kochersperger, L.M., Dower, W.J., Barrett, R.W., and Gallop, M.A. (1993) Generation and screening of an oligonucleotide-encoded synthetic peptide library. Proceedings of the National Academy of Sciences of the United States of America, 90,10700-10704 (c) Nielsen, J., Brenner, S., and Janda, K.D. (1993) Synthetic methods for the implementation of encoded combinatorial chemistry. Journal of the American Chemical Society, 115, 9812-9813. 

All the spectroscopic approaches applied for structural characterization of mixtures derive from methods originally developed for screening libraries for their biological activities. They include diffusion-ordered spectroscopy [15-18], relaxation-edited spectroscopy [19], isotope-filtered affinity NMR [20] and SAR-by-NMR [21]. These applications will be discussed in the last part of this chapter. As usually most of the components show very similar molecular weight, their spectroscopic parameters, such as relaxation rates or selfdiffusion coefficients, are not very different and application of these methodologies for chemical characterization is not straightforward. An exception is diffusion-edited spectroscopy, which can be a feasible way to analyze the structure of compounds within a mixture without the need of prior separation. This was the case for the analysis of a mixture of five esters (propyl acetate, butyl acetate, ethyl butyrate, isopropyl butyrate and butyl levulinate) [18]. By the combined use of diffusion-edited NMR and 2-D NMR methods such as Total Correlation Spectroscopy (TOCSY), it was possible to elucidate the structure of the components of this mixture. This strategy was called diffusion encoded spectroscopy DECODES. Another example of combination between diffusion-edited spectroscopy and traditional 2-D NMR experiment is the DOSY-NOESY experiment [22]. The use of these experiments have proven to be useful in the identification of compounds from small split and mix synthetic pools. 

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]. 

The most general method of encoding a chemical library is based on a small device which, upon activation, emits a given radiofrequency (rf). This device needs to be attached to the synthetic platform (beads, resins, tubes, etc.) on/in which the synthesis of products takes place. The device (which is 8 mm x 1 mm in size) contains three components first, a memory for alphanumeric codes second, a rectifying circuit which absorbs radiofrequency energy and converts this energy into electrical energy. The latter is used by the third component, an antenna, to transmit the code to an external receiver that is linked to a computer. 

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