Library encoding

Fig. 3.3 Synthetic scheme for mass-encoded library NGL127A443 containing isobaric positional isomers 1 and 19. Reprinted from [40] with permission from Elsevier.

Scheme 1. General synthetic and encoding/decoding scheme of encoded library.

Taylor and Morken extended the use of IR-thermography to the monitoring of the change in the heat of reaction on and in the surroundings of a bead carrying an active catalyst (Figure 5.4.4) [13]. In a search for acylation catalysts an encoded library of 3150 different potential nucleophilic catalysts was prepared by the split-and-mix procedure and tested for their acylation properties. The library beads were spread in a reaction solution of chloroform-ethanol-triethylamine-acetic anhydride, 40 6 6 3, and monitored with an IR camera. Whereas no detectable thermal... 

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. 

Synthesis and screening of orthogonal and binary encoded libraries... 

Screening large pools of compounds has several disadvantages, and often results in missed or false activities. To obviate such limitations, different pooling and structure identification strategies such as orthogonal libraries and binary encoded libraries have been developed and reported to provide examples of bioactive molecules. 

Sequence spaces may also be defined based on encoded libraries. In such libraries, different molecular species are labeled with readable tags that record the sequence of... 

Screening the encoded library produced interesting structures to build an SAR and to design focused libraries of binders for the artificial receptor, but some limitations of these linkers for applications different from peptide chemistry are clearly evident. The carbonate bond connecting the electrophone tag and the photocleavable linker (Figure 9.8) is sensitive to many organic reaction conditions, and the carboxylate requires an amino- or hydroxy function to be linked to the resin after each synthetic step to be encoded. 

The library was tested for ACE inhibitory activity through cleavage of single beads in 96-well plates, and approximately 1000 beads were cleaved. The most active compound identified was the same obtained with iterative deconvolution [41], but additional structures were obtained producing data for a preliminary SAR. A detailed comparison between the results obtained from this encoded library and from the same (non coded) library via iterative deconvolution will be presented in a following section (page 225). 

Garigipati and Adams [61] reported a chemical encoding procedure, based on novel photochemically cleavable aryl sulfonamides as inert tags with a robust and reliable chemistry. An example of a 1000-member encoded library was provided without experimental details, so additional applications of these chemical tags need to be disclosed in order to have a better understanding of their strengths and limitations. 

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... 

Atuegbu A, Maclean D, Nguyen C, Gordon EM, Jacobs JW, Combinatorial modification of natural products preparation of unencoded and encoded libraries of Rauwolfia alkaloids, Bioorg. Med. Chem., 4 1097-1106, 1996. 

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. 

Contemporaneously with these recent discoveries, our laboratory has used directed evolution by random sequence mutagenesis of a region of human TS near the catalytic cysteine (position 195) to produce novel 5-FU resistant TS mutants. A plasmid-encoded library of TS mutants was constructed using an oligonucleotide-based random mutagenesis technique. The end product of this process was a family of over 2 million... 

Figure 2. Encoded libraries prepared through split synthesis.

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