Papers #6, #7, and #8 report the advantages of using "quenching reagents" attached to polymer beads as a quick and easy way of purifying a library of surplus reagents and impurities.

   In the original method, a library was built up on polymer beads, to which the substrate molecule was attached, via a link, and then the various components added to give all possible combinations. Generally these had then to be released from their polymer tethers, before being tested against the target. While combinatorial chemistry enables hundreds and thousands of molecules to be made together, in practice it was often difficult to achieve. Choosing the right polymer support, finding the right link, and attaching the substrate were only the start. At each stage it was necessary to add excess reagents to drive reactions to completion, then to remove the excess--and any unwanted by-products--before adding the next reagent…and so on, until the desired library had been constructed. Anything which could simplify this procedure would clearly be of great benefit.

   Papers #6, #7, and #8 are all concerned with the same breakthrough: using a polymer-bound material selectively to remove unwanted materials from reaction products. In this way the library is built by starting with the substrate in solution, and the many variants are made using traditional methods. Then excess polymer-bound quenching reagent is added to mop up the unwanted reactants, after which it can simply be filtered off, leaving the combinatorial mixture free to move on to the next stage.

   Paper #6 announced the new technique, and came from the group headed by Stephen Kaldor and Miles Siegel, based at the labs of the international drug company Eli Lilly in Indianapolis, Indiana. They showed that the method worked with amine alkylations, in which solid supported isocyanates could scavenge excess amine reagents, or vice versa. After they had done their work, the beads were easily filtered off, leaving a solution that could be monitored by ordinary chemical analysis methods, something that it is not possible to do when the product is attached to a polymer bead.

   Papers #7 and #8 were submitted on the same day for publication, and appeared back-to-back in the same issue of Journal of the American Chemical Society. The paper from Daniel Flynn’s group at the labs of the drug company Searle in St. Louis, Missouri, and Skokie, Illinois, also concentrated on the reactions of amines with other reagents, as did that of John Hodges and John Booth, of Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan. Readers who wish to get a grasp of the importance and use of polymer-supported quenching reagents should read the Hodges and Booth paper, which is a model of clarity.

   The three papers promise a return to purification methods which give solution-phase combinatorial synthesis other advantages over the solid-phase alternative. In addition to easy monitoring and spectroscopic analysis, it again permits the use of "protecting groups" to shield the sensitive parts of a molecule from attack. Not only that, but relative to traditional chromatography, polymer-support quenching offers a method of purification that uses less solvent, less solid support, and does not need the collection of multiple fractions. This, argue Hodges and Booth, more than compensates for the increased cost of their resins, which in any case can be made in large quantities from cheap materials. And while the final products may not be quite so pure, they are pure enough to go forward for screening as potential drugs.