Focussed library synthesis

Then there is focussed library synthesis, FLS. In its broadest sense this involves synthesis of a larger number of compounds than TOS, often using solid-phase chemistry (Box 1), but where all the products are still quite similar. FLS allows more exhaustive exploration than TOS of a relatively small volume of biological chemical structure space. Peptide library synthesis can be considered one of the first examples of this category because an underlying polypeptide backbone, which is the same for all members of the library, is elaborated with variable side-chains. Taking its lead from peptides and oligo-nucleotides, much effort has been directed over the last decade towards library synthesis with substrates bound to solid supports, to facilitate... 

The scaffold extractor generates scaffolds, extended scaffolds and frameworks. The extended scaffolds, imlike the conventional Bemis Murcko scaffold [72], retain cormection information and are used in focussed library synthesis (Fig. 2.27). 

Contributions by R. Joseph and P. Arya as well as M. A. Koch and H. Waldmann focus on synthetic aspects towards lead structures originating from natural product-derived scaffolds. R. Joseph and P. Arya refer to two complementary approaches, the synthetic access to focussed libraries around bioactive natural product cores, and diversity-oriented synthesis aiming at 3D scaffold diversity for hit generation, respectively. On the other hand, M. A. Koch and H. Waldmann emphasise the correlation of natural product-based library concepts with structural features of targeted protein domains, thus strengthening the privileged structure concept from a bioorganic viewpoint. 

The use of parallel synthesis approaches (arrays or focussed libraries) in the lead identification field is widespread with many examples published in the chemistry literature and presented at conferences. 

When performing a synthetic combinatorial chemistry experiment, several basically different strategies may be followed to create a library of compounds. The most commonly used are mixelsplU (or split and pool) synthesis [1] masking strategies [15, 16] and parallel synthesis. In this chapter, the attention is focussed on the application of parallel synthesis to catalysis in the liquid phase. 

With the trend in dmg discovery towards smaller focussed compound libraries and the increasing importance of solution-phase techniques in parallel synthesis, fully automated systems may have lost some of their appeal. Nevertheless, a few instruments are on the market... 

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