Combinatorial Chemistry Review

Parallel Solution Phase Synthesis

Manual or automated approaches can be used for the parallel preparation of tens to hundreds of analogues of a biologically active substrate. The products are synthesised using reliable coupling and functional group interconversion chemistry and are progressed to screening after removal of solvent and volatile by-products. Parallel and orthodox synthesis is compared below.

low throughput screening High Throughput Screening

Orthodox synthesis usually involves a multistep sequence, e.g. from A through to the final product D, which is purified and fully characterised before screening. The next analogue is then designed, guided by the biological activity of the previous compound, prepared, and then screened. This process is repeated to optimise both activity and selectivity.

In contrast parallel analogue synthesis involves reaction of a substrate S with multiple reactants, R1, R2, R3 Rn, to produce a compound library of n individual products SR1, SR2, SR3 SRn. The library is screened, usually without purification, and with only minimal characterisation of the individual compounds, using a rapid throughput screening technique.

Panlabs have recently disclosed an interest in making large number of compounds as individual components using parallel, reliable solution chemistry. Reactions are pushed to completion by the use of excess quantities of the reactive reagent, and are isolated by solvent - solvent extraction. There is no further purification, and thus they prefer to describe these samples as "reaction products".