Combinatorial libraries building

A fundamental recipe for preparing combinatorial libraries is the randomization approach known as portion mixing. This technique is also called sptit-and-mix or divide-and-combine [4,5]. In this approach, solid-phase resins containing combinatorial library building blocks are portioned out, coupled, and combined to produce a combinatorial library of compounds. It is a way to synthesize a large... 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

The head-to-tail-coupling reactions described above are potentially useful in the design of dynamic combinatorial libraries. Features of these reactions include the rapid and reversible formation of carbon-carbon bonds, multifunctional ene-imine building blocks, and formation of stereo centers upon ene-imine linkage. Support for template-directed synthesis utilizing ene-imine building blocks is the formation of a poly ene-imine species that could recognize 3 -GGA-5 sequences of DNA.48 It is noteworthy that some polyene-imines are helical and could form a triple helix with DNA. 

Figure 1. General schematic of a combinatorial library prepared from a small set of building blocks.

The preparation of a combinatorial library requires the simultaneous manipulation and isolation of many different compounds. A uniform sequence of operations is required to efficiently prepare and isolate each member of the library. In contrast the traditional synthesis of compounds utilizes conditions tailored specifically to the compound desired. A key challenge for library preparation is the development of a robust synthesis sequence that cleanly incorporates chemical building blocks containing a diverse range of chemical functionality in high yields. Equally important are the development of uniform and efficient methods to isolate intermediates and products from solvents, reagents, and byproducts. 

The observed differences create a basis for a rational selection of building blocks for synthesis of combinatorial libraries enriched in target-specific motifs. The quantitative structure-activity discrimination function found at this stage of our study can be used for effective search of reactive monomers possessing the desired physicochemical and spatial parameters. 

Grote, Z. Scopelliti, R. Severin, K. Adaptive behavior of dynamic combinatorial libraries generated by assembly of different building blocks. Angew. Chem. Int. Ed. 2003,42, 3821-3825. 

Hochgiirtel, M. Biesinger, R. Kroth, H. Piecha, D. Hofmann, M. W. Krause, S. Schaaf, O. Nicolau, C. Eliseev, A. V. Ketones as building blocks for dynamic combinatorial libraries Highly active neuraminidase inhibitors... 

Figure 3.25 Racemic dynamic combinatorial library targeting (-)-adenosine. Left Racemic porline containing dipeptide library building block. Middle Various enantiomeric oligomers formed through reversible hydrazone exchange. Right The SS enantiomer selected upon equilibration with (-)-adenosine.

Liu, J. West, K. R. Bondy, C. R. Sanders, J. K. M. Dynamic combinatorial libraries of hydrazone-linked pseudo-peptides Dependence of diversity on building block structure and chirality. Org. Biomol. Chem. 2007,5, 778-786. 

Another recent concept is the template-directed synthesis from dynamic combinatorial libraries. Here, one or several building blocks that are prone... 

Generate a trial solution to the underlying problem. For combinatorial library design, a random selection of a subset of building blocks is generated. 

Calculate the value of a fitness function (Fcurr) that characterizes the quality of the trial solution to the underlying problem (e.g., the diversity or predicted activity of the combinatorial library built upon the selection of building blocks from step 1). 

Perturb (i.e., slightly modify) the trial solution to obtain a new solution (e.g., a part of the selected building blocks are changed to other building blocks in order to build a new combinatorial library). 

Computational methods described in this work are tested using a tripeptoid combinatorial library described by Zuckermann et al. (35). These authors described chemical structures of 24 amines used as building blocks for the pep-toid synthesis. The common Markush structure of tripeptoids is shown in Fig. 3 where R1, R2, and R3 are the alkyl portions of primary amines used as building blocks. The structures of the building blocks are shown in Fig. 4 and we followed the abbreviations used in the original publication. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

Since diversity is a collective property, its precise quantification requires a mathematical description of the distribution of the molecular collection in a chemical space. When a set of molecules are considered to be more diverse than another, the molecules in this set cover more chemical space and/or the molecules distribute more evenly in chemical space. Historically, diversity analysis is closely linked to compound selection and combinatorial library design. In reality, library design is also a selection process, selecting compounds from a virtual library before synthesis. There are three main categories of selection procedures for building a diverse set of compounds cluster-based selection, partition-based selection, and dissimilarity-based selection. 

Fragment-based design, where the constituents of the compounds (scaffolds and functional groups/substituents) are docked in the binding site and then linked together to build combinatorial libraries. 

Synthesis of a three-step combinatorial library of 960 compounds using 10, 8, and 12 building blocks in the first, second, and third combinatorial steps, respectively, consists of the following steps ... 

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