Compound Libraries and Combinatorial Chemistry

As mentioned earlier in this chapter, the major pharmaceutical companies are interested in accumulating large numbers of compounds with a great diversification of chemical structures for use in establishing new leads for drug development. These chemical libraries can be prepared synthetically or biosynthetically and screened for pharmacological activity in a variety of different formats (e.g., libraries of soluble molecules; libraries of molecules tethered to resin beads, silica chips, or other solid supports; or recombinant peptide libraries on bacteriophage and other biological display vectors) (9). Some companies exchange small collections of compounds to increase the different classes of agents available for screening, and collections of compounds or plant extracts are available from independent brokers (10).

These libraries are valuable resources, because they may contain the new protypes for new therapeutic classes of drugs (11). Each year, new biological targets are discovered; therefore, these libraries are constantly being rescreened year after year in novel assays. The systematic and repetitive, covalent connection of a set of different building blocks of varying structures to each other in order to yield a large array of diverse molecular entities is referred to as combinatorial chemistry (9). The primary strategies of combinatorial chemistry are to make a large number of chemical variants all at one time, to test them for biological activity, and to isolate and identify the most promising compounds for further development (12). These chemical libraries contain so many compounds that special methods of cataloging, storage, and retrieval are required to use the library effectively. Two general methods of synthesis are used to create combinatorial libraries. The first is split synthesis, in which compounds are assembled on surfaces of beads or particles (12). In a split-and-combine technique, either specific mixtures or individual compounds are synthesized on single beads. In a series of steps, the beads are divided into several groups, and a new building block is added. The different groups of beads are then recombined and separated again into new groups. The next building block is added, and the process continues until the desired combinatorial library has been assembled. Each bead in the library holds multiple copies of a single library member (12). Split synthesis is generally used to produce small quantities of a relatively large number of compounds, requires a solid support, and permits assays to be performed on pools of compounds.

The second method for creating combinatorial libraries is parallel synthesis. In this process, which is usually automated, compounds are synthesized in separate vessels (most recently microtiter plates, but solid support can be used) with out remixing. Parallel synthesis yields larger quantities of a relatively small number of compounds, and can be done on either solid or liquid support. Assays can be done on individual compounds (12). Excellent reviews of this subject have been published (13-16).

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