Screening solid phase synthesis

Solid Phase Synthesis for High Throughput Screening. 256... 

COMBINATION OF THE SCREENING APPROACH WITH COMBINATORIAL SOLID PHASE SYNTHESIS OF CATIONIC LIPIDS... 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

Lynas, J. F., Martin, S. L., Walker, B., Baxter, A. D., Bird, J., Bhogal, R., Montana, J. G., Owen, D. A. (2000) Solid-phase synthesis and biological screening of N-a-mercaptoamide template-based matrix metalloprotease inhibitors. Comb Chem High Throughput Screening 3, 37—41. 

An important criteria in solid-phase synthesis is product purities immediately after cleavage from the support. Ideally, the target compound should be cleaved into a solvent-reagent system that can be easily removed, usually by evaporation. Solvents/cleavage reagents that are difficult to remove may compromise subsequent biological screening of the libraries. Consequently,... 

Various techniques have been developed that enable the rapid preparation and screening of large numbers of different compounds by parallel solid-phase synthesis. Reactions can, for instance, be conducted in an array of reactors such as that sketched in Figure 1.1. Synthesizers with up to approximately 600 discrete reactors are commercially available these enable the automated preparation of compound libraries containing up to 0.1 mmol of each compound. Discrete reactors are also well suited for the development and optimization of solid-phase chemistry. 

For the fast identification of lead compounds for novel, small molecule enzyme inhibitors or other ligands for proteins, the screening of large and diverse arrays of compounds prepared on insoluble supports is one of the most efficient approaches.1-8 Parallel solid-phase synthesis has been found to be particularly well suited for the preparation of such arrays of diverse compounds since multistep synthetic sequences on insoluble supports can be conducted on fully automated synthesizers. 

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. 

Recent literature contains a multitude of examples of synthetic organic methodologies which have been optimized and applied to the solid-phase synthesis of combinatorial libraries [2]. In fact, the production of a number of these libraries has been realized on such systems as the Multipin SPOC [8], the DIVERSOMER [9] and the OntoBLOCK [10], All three apparatuses allow the automated production of spatially dispersed combinatorial libraries and facilitate the isolation, identification, screening and archiving of single compounds in distinct physical locations which are crucial factors during lead discovery and optimization. 

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