Screening solution-phase synthesis

High Throughput Screening (HTS) Techniques Overview of AppUca-tions in Chemical Biology Solution-Phase Synthesis of Biomolecules... 

CD Garr, JR Peterson, L Schultz, AR Oliver, TL Underiner, RD Cramer, AM Ferguson, MS Lawless, and DE Patterson. Solution phase synthesis of chemical libraries for lead discovery. J Biomol Screen 1 179-186, 1996. 

If small or medium libraries for lead optimization are demanded and all synthetic products are to be screened individually, most often parallel synthesis is the method of choice. Parallel syntheses can be conducted in solution, on solid phase, with polymer-assisted solution phase syntheses or with a combination of several of these methods. Preferably, parallel syntheses are automated, either employing integrated synthesis robots or by automation of single steps such as washing, isolation, or identification. The latter concept often allows a more flexible and less expensive automation of parallel synthesis. 

The first report of resin capture in solution-phase chemical library synthesis involved the covalent capture of solution-phase Ugi reaction products onto a functionalized polystyrene resin.73 Excess reactants, reagents, and reagent byproducts were washed away from the resin-captured intermediates. Further manipulation and release afforded purified solution-phase products for screening. More recently the same group reported on resin capture as a technique for the preparation of tetrasubstituted olefin libraries.74 75 As illustrated in Scheme 5, m-vinyl di-boryl esters were reacted with aryl halides (R3ArX) in parallel Suzuki reactions, leading to solution-phase intermediates. Another Suzuki reaction, this time with the... 

Another use for combinatorial libraries has been the screening of peptides for antimicrobrial properties. In this case, the design of the library is based on antimicrobial peptides found in nature. A combinatorial synthesis is used to find alternative unnatural amino acids expected to mimic the antimicrobial properties.23 Peptide libraries also have been used to find compounds that could bind the lytic peptide mellitin.24 The library was synthesized in solution phase, purified, and evaluated using time-of-flight mass spectrometry (TOF-MS). The sequences determined to bind to mellitin contained hydrophobic pairs. By binding to mellitin, they were able to prevent the cell-surface mellitin interaction. This is an example of a peptide library able to afford compounds that interact with other small peptides without having to find an interacting protein first. 

Such products may be screened directly without any further purification. Because no purification on the final products is required in such instances, parallel solid-phase synthesis can be used to prepare arrays of compounds with a broad range of lipophilicity, charge, and molecular weight.9 Such arrays would be difficult to prepare by parallel solution-phase chemistry not only because each compound would require a different work-up strategy, but also because the purification of small, hydrophilic molecules is often a difficult task. 

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