Arrays libraries Focused, combinatorial

The isolation of natural products from organisms generally yields compound libraries covering large areas in diversity space. In some cases, sets of structurally related natural compounds are isolated (see Section 5.4) that are suitable for an initial analysis of SAR. Mostly, however, further structural variations and focused libraries are required for in-depth determination of SAR and lead optimization. The new paradigm for creating such small-molecule libraries by combinatorial and parallel synthesis has been successfully apphed to natural product synthesis and enabled chemists to build arrays of derivatives based on a common natural product template. ... 

Cluster-based and dissimilarity-based methods for compound selection were first discussed in the Eighties but it is only in the last few years that the area has attracted substantial attention as a result of the need to provide a rational basis for the design of combinatorial libraries. The four previous sections have provided an overview of the main types of selection method that are already available, with further approaches continuing to appear in the literature. Given this array of possible techniques, it is appropriate to consider ways in which the various methods can be evaluated, both in absolute terms and when compared with each other. A method can be evaluated in terms of its efficiency, /.< ., the computational costs associated with its use, and its effectiveness, /.< ., the extent to which it achieves its aims. As we shall see, it is not immediately obvious how effectiveness should be quantified and we shall thus consider the question of efficiency first, focusing upon the normal algorithmic criteria of CPU time and storage requirements. 

These libraries contain a relatively small number of individuals (typically tens to hundreds) and are almost always prepared as discrete libraries using parallel synthesis and automated or semiautomated devices. Focused libraries are predominantly prepared in solution because of the easier shift from classical organic synthesis to solution-phase combinatorial chemistry, while automated purification procedures for relatively small arrays of discrete compounds in solution are common nowadays. The... 

When The combinatorialization, usually in small solution- or solid-phase arrays, of the planned synthesis is not particularly demanding for focused libraries. Moreover, an active compound from a primary library is often the stmctural information around which the focused library has been designed so that a detailed chemical assessment has already been performed. The use of focused libraries should become more and more frequent given the simplicity of their synthesis and the significant impact they may have on the progression of many projects. 

Fig. 15.1-3 Schematic visualization of the various concepts to address chemical and biological space (shaded areas) in drug discovery. Medicinal chemistry focused on compound series (red dots) that had shown activity in pharmacological assays and compound optimization was driven by a tight feedback from biological experiments, leading to a focused nonarrayed addressing of chemical space. The combinatorial promise was to systemically explore the chemical space with diverse arrays of compounds (blue dots) to find the suitable starting points. Analysis of combinatorial chemistry libraries showed their limited...

Out of the combinatorial chemistry boom came the framework for modem solid-phase organic synthesis. While a lot of the early work with SPOS focused on reliable and relatively straightforward peptide coupling reactions, the ambitious library syntheses of the 1990s required access to a much more extensive array of solid-phase reactions. That decade saw initial strides made in adapting many well-known solution-phase reactions for use in the solid-phase arena, development that continues to the present day, " and a move beyond peptide and nucleotide chemistry toward preparation of small molecule libraries on solid phase. 

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