Primary libraries

McGregor, M. J., Muskal, S. M. Pharmacophore fingerprinting. 2. Application to primary library design. 

As an example, the bifimctional epoxy ester core (+)-2 was reacted with building blocks 3-18 to yield solution-phase library NGL127A443 containing nominally 512 substitutionally and stereochemically unique compounds (Figs. 3.3, 3.4). Of these, 82% have a molecular weight unique to 0.050 amu. This library was combined with four other 500-member libraries to form a 2500-member primary library that was screened against the important antibacterial target dihydrofolate reductase (DHFR, also known as Fol-A). 

As already presented in the section on Design , for the strategy WGS 2, a primary library containing 490 catalysts was designed by partitioning the search space. In Fig. 10.9, the catalysts are ranked as a function of the CO conversion. 

The decoration of a central scaffold is illustrated by the triazine library Lll reported by Gustafson et al. (46) where trichlorotriazine was sequentially substituted with anilines (Ar), primary aliphatic amines (Ri), and secondary aliphatic amines (R2,3). The library, made up of 20 x 16 x 20 = 12,800 compounds, was prepared as discretes (Fig. 4.12) and used as a primary library to be screened on various assays. The introduction of sugars, dipeptides, and a-ketoamides among other amine substituents in Lll created diversity in the components even though each of them shares a common 2,4,6-triaminotriazine scaffold. Examples of individuals from LI 1 are provided in Fig. 4.12. Such a decoration library can be made when a suitable scaffold is available in large amounts, either commercially or through a simple synthetic route. Constrained... 

Another decoration pool library L23 was reported by Nestler (49), who presented the appendage of a peptidic chain to the two hydroxylic functions of a steroid scaffold (Fig. 4.15). The library was made up of 10 x 10 x 10 x 10 = 10,000 individuals using a chemical encoding method (39) and L-a-amino acids as monomer sets (R1-R4). The assay of the library as a source of artificial two-armed receptors for enkephalin-related peptides produced positives with micromolar affinity. Much larger libraries could be obtained by simply increasing the monomer sets and the length of the two arms this could lead to a primary library of peptide-binding artificial receptors similar scaffolds have been repeatedly exploited for combinatorial purposes (50-52). 

Whenever a library is designed in a particular formaL some basic questions should be addressed to justify its synthesis. We will address them first in theory then we will apply the same principles to a published example of a primary library. 

Why A primary library can be planned for many purposes. Sometimes the project goal is purely academic, that is, simply to open a new combinatorial synthetic route and to report it. This respectable option allows complete freedom to prepare any primary library, with no constraints dictated by parameters such as application, cost, or resources. We will not comment further upon this approach in this section. More often, though, a primary library is prepared as a source of relevant active molecules on various biological targets. This obviously necessitates the availability of several robust and reliable HTS assays for these targets, as well as the synthetic resources, the analytical resources, and the instrumentation to ensure the successful synthesis and analytical characterization of the library. 

When The combinatoriaUzation of the planned synthesis is often long and arduous for primary libraries, so several applications must be available for the library to compensate for this major undertaking A single target would not justify the efforts required, and hence another library format would be preferable. 

How The large number of components of primary libraries is more suitable for SP pool libraries, but each library has to be designed keeping in mind the available equipment and the expertise of the chemical resource(s). The same is true for the analytical methods used to check every step of the library synthesis. 

The primary library shown in Fig. 5.2, which was reported by Baldwin (1), was clearly designed as a source of biologically active molecules on several targets (why), thus compensating the efforts required for the chemical assessment and for a satisfactory characterization (when). The SP library was prepared in pools using chemical encoding (4, 5) to produce a population of around 62,000 individuals (how). The synthetic scheme was composed of both simple and more complex SP steps, and several monomer sets (A-F, Fig. 5.2) were used (what). These monomers were either commercially available or easily prepared from commercial precursors, while the library benzopyranic core was formed during the synthesis (how much). 

The primary library synthesis is then carried out using any of the techniques that will be illustrated in detail in the next three chapters for solution- or solid-phase, pool or discrete libraries. Many choices in terms of instrumentation or automation are available, and each of them may afford high-quality results. The same is true for analytical quality control, which determines the synthesis outcome and decides if the hbrary is suitable for screening against desired targets. 

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