STRUCTURE-CONTROLLED AUTOMATED PURIFICATION OF PARALLEL SYNTHESIS PRODUCTS IN DRUG DISCOVERY

Extensive automation of both random and rational drug discovery strate gies greatly increases the number of compounds entering biological scr eens. Although parallel synthesis (one compound per well) strategies e liminate the deconvolution step necessary when pooled libraries are sc reened, parallel synthesis products are usually screened as crude mixt ures, because purification slows the process of lead discovery. Screen ing crude products is sometimes complicated by synergies and interfere nces between compounds. Screening pure compounds is the only sure rout e to immediate, reliable structure - activity relationships. Automated purification strategies are designed to limit or remove the purificat ion bottleneck between synthesis and screening. In this paper, a works tation is described which uses a combination of UV absorbance and mass spectrometric data to make real-time decisions for HPLC fraction coll ection, allowing selection of compounds based on mass or substructure. This methodology has demonstrated success with parallel synthesis pro ducts in drug discovery applications. (C) 1998 John Wiley & Sons, Ltd.