Library, combinatorial chemistry formation

Solid support Combinatorial chemistry Formation of libraries possible [124, 125]... 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

While this may in fact be the case for natural product mixtures, it is rarely the case when dealing with synthesized mixtures. Despite our attempts to create real molecular diversity in the test tube, our efforts have not even begun to anticipate the true diversity of atomic connectivity within "drug space" (estimated to be of the order of 1063 unique compounds, theory, famously in this case, greatly outpacing the amount of matter in the universe). Thus, combinatorial chemistry was never practically able to produce true chemical diversity and compounds produced in such library format ended up looking very much like one another, with the attendant similarities in biological activity profiles. 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

With these selected examples as context, it became clear to several laboratories in the mid-1990s that one should be able to combine reversible formation of compounds (exchange processes) and a selection method with the then rapidly developing field of combinatorial chemistry to produce equilibrating libraries that would evolve based on some selection process. Thus, dynamic combinatorial chemistry or DCC, as it came to be called, evolved from a number of lines of research into the diverse and vibrant field it is today. 

As shown in Fig. 16.6, we planned to use a pre-registered combinatorial chemistry protocol (LJ0194) to synthesize the targeted library. PGVL Hub allowed us to easily search and load this pre-registered reaction scheme into a design session without the need to draw a reaction scheme required for product enumeration (see Fig. 16.7). Even for this simple reaction, a simple reaction scheme drawn by users may not be sufficient to ensure proper formation of product structures in the case where bonds associated with chiral centers are near the reactive sites on the reactants. 

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

II. Product Summaries BCI specializes in software for analysis of the structural diversity of large chemical dataset and combinatorial chemistry libraries. BCI s software covers Chemical Structure Fragments and Fingerprinting, Diversity Analysis, Cluster Analysis, and Structure or Reaction query format conversion (MOLSMART). 

Dynamic combinatorial chemistry (DCC) is a rapidly emerging field that offers a possible alternative to the approach of traditional combinatorial chemistry (CC).32 Whereas CC involves the use of irreversible reactions to efficiently generate static libraries of related compounds, DCC relies on the use of reversible reactions to generate dynamic mixtures. The binding of one member of the dynamic library to a molecular trap (such as the binding site of a protein) is expected to perturb the library in favor of the formation of that member (Figure 29.1). 

Eliseev AV, Lehn JM, Dynamic combinatorial chemistry Evolutionary formation and screening of molecular libraries, Curr. Top. Microbiol. Immunol., 243 159-172, 1999. 

As discussed elsewhere, the combinatorial chemistry industry is fragmented, consisting of four major types of companies, separated essentially by whether they make or use libraries. This has resulted in large numbers of alliances between these companies, and the characteristics of these alliances as business formats are developed elsewhere in this chapter. 

This dynamic process is commonly known as constitutional dynamic chemistry (CDC). While the concept of dynamic covalent chemistry defines systems in which the molecular (or supramolecular) reorganization proceeds via reversible covalent bond formation/breakage, dynamic systems based on noncovalent linkage exchanges define the concept of dynamic noncovalent chemistry. Dynamic combinatorial chemistry (DCC) can be defined as a direct application of CDC where libraries of complementary functional groups and/or complementary interactional groups interexchange via chemical (i.e., covalent) reactions or physical (i.e., noncovalent) interactions. 

The previous chapters have shown how combinatorial technologies have always been associated with chemistry in the SP and how this chemistry is flexible enough to provide libraries in many formats. More recently, there has been growing interest in libraries of small organic molecules prepared under homogeneous reaction conditions. These libraries are usually called solution-phase libraries and will be discussed in this chapter to demonstrate how they present a useful alternative to SP libraries and how they can provide the chemist with more options with regards to the choice of library format. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

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