Pools of compounds

Chemical templates are being increasingly employed for the development of dynamic combinatorial libraries (DCL) [94-98]. These (virtual) libraries of compounds are produced from all the possible combinations of a set of basic components that can reversibly react with each other with the consequent potential to generate a large pool of compounds. Because of the dynamic equilibria established in a DCL, the stabilization of any given compound by molecular recognition will amplify its formation. Hence the addition of a template to the library usually leads to the isolation of the compound that forms the thermodynamically more stable host-guest complex (see Scheme 37). 

An additional complication of the bioassay of mixtures, be they natural extracts or combinatorial in nature, is that any activity present in a pool of compounds must still be assigned to the individual components to render the screening exercise useful for Drug Discovery. This is more straightforward with respect to combinatorial mixtures due to the fact that, by definition, the structural type is known, and what is not known is just the specifics of the attachment of monomer. Nonetheless, structure elucidation of active components must be made and this has traditionally been done through what is referred to as "deconvolution."... 

Lifely, R., Miller, L., and Ramsden, N. Strategic pooling of compounds for high-throughput screening. J. Comput. Chem. Inf Sci. 1999, 39, 897-902. 

While the methods described in this chapter have been optimized for affinity selection-MS using continuous SEC, they are readily adaptable to spin-column, gel permeation, or other well validated and highly accessible two-stage AS-MS designs. The use of AS-MS for studying protein-ligand interactions, especially for the discovery of ligands from pools of compounds, has been reported by a number of experts in the pharmaceutical industry and academia over the past decade. 

Under investigation at the present time is virtually every compound being studied in depression and in panic disorder. Perhaps new and effective treatments for social phobia will arise from this same pool of compounds. 

Screening large pools of compounds has several disadvantages, and often results in missed or false activities. To obviate such limitations, different pooling and structure identification strategies such as orthogonal libraries and binary encoded libraries have been developed and reported to provide examples of bioactive molecules. 

Combinatorial chemistry is the production of libraries of compounds that represent permutations of a set of chemical variables. These variables include the nature of the substituent in a particular molecule, both in type and size, changes in the components in a mixture of materials, e.g. in ceramics and changes in process parameters, e.g. temperature, pH etc. Chemical libraries are usually created by one of two methods split and mix or parallel synthesis . Split and mix synthesis is used to produce small quantities of a relatively large number of compounds and requires assays to be performed on pools of compounds. Parallel synthesis is used to produce libraries... 

Fig. 5 A pool of compounds containing imines I and 3 and nitrones 2 and 4 can exchange freely in CD2C12 saturated with p-toluenesulfonic acid monohydrate at 273 K. Material can be transferred irreversibly to a pool of products, present in the same solution, that cannot be interconverted or returned to the exchange pool, through reaction of nitrones 2 or 3 with an appropriate maleimide (5a or 5b). When maleimide 5b is used as the dipolarophile, replicator trans-lb is formed in the product pool and this species can act as a catalyst for its own formation. (Reproduced from [45])...

Validation of the compounds in HTOS libraries has become an area that is receiving more attention. Because of the movement away from pools of compounds (mixtures) to discrete compounds for SAR development, quality control and quality assurance of the samples has become an issue. The issue of quality vs. quantity in HTOS has been discussed in a recent paper by MacDonald et al. (71). Bauer has described an information management system that incorporates several quality checks on the data generated by HTOS systems (72). 

The hydrolytic kinetic resolution addressed a long-standing problem in enan-tioselective epoxide synthesis. The ability to access almost any terminal epoxide or 1,2-diol in high enantiopurity greatly expanded the chiral pool of compounds available for asymmetric synthesis. Equally important was the demonstration of practicality and efficiency that renders the ARO of a racemic mixture a synthetically viable approach. 

Lessons learned from natural products dereplication and prioritization in high-throughput assays can also be applied to the deconvolution problems, faced by combinatorial chemists when assaying pools of compounds. With limited resynthesis capabilities, not every active pool can be followed up, and the use of prioritization methods will be required, similar to those outlined above. 

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