A technique that was very popular but had diminished in significance over the past 5 years is the technique of encoding. In theory, this should be a very useful and concise method for the structure elucidation of active compounds within a resin-bound mixture. In its simplest form, encoding involves the orthogonal placement of chemical identification tags on resin beads containing the target compound, with the identity of the individual monomers that make up the final product being "encoded" by the very constitution of the tags themselves. This technique has proven fairly tricky because it requires that discrete compounds prepared on individual beads in mixtures be assayed either while still attached to the bead of origin or else cleaved from that single isolated bead and assayed while retaining the bead itself for analysis. Why is this so? Because the orthogonal synthesis strategies for analyte and tag leave the tag still attached to the bead, ready for analysis should the analyte prove to have biological activity. Another technological hurdle for the encoding technique has been the obvious requirement that the tag be much easier to analyze and identify than the test compound itself (otherwise one could simply use some analytical technique to identify the structure of the product rather than an inactive chemical surrogate). This has been done most successfully by a number of techniques including secondary amide strategy, mass encoding, polyhalogenated aromatics, and radio-frequency tagging. The fact that encoding techniques for compound identification in the split-and-mix protocol is so specialized and often requiring extraordinary hardware is punctuated by the fact that whole companies or divisions have been set up or repositioned to produce, promote, and capitalize the individual encoding strategies.
It may be conjectured at this point that the vast majority of expenditure by the pharmaceutical and biopharmaceutical industries on the "combinatorial chemistry revolution" has been in the areas of split-and-mix synthesis, deconvolution, and encoding or decoding and much novel and innovative equipment designed to facilitate these techniques. Ultimately, while these techniques produced a great number of compound libraries for evaluation in the drug discovery setting, often only nanograms of final compound — quickly depleted after only a few rounds of screening — were procured. Furthermore, the production of minute quantities of compounds outstripped our understanding of the optimal methods of storing them. The "good enough" solution was to store these compounds in solubilized form. The ubiquitous solvent DMSO seemed to provide the perfect answer; miscible with water in all proportions and typically innocuous to biological systems in low concentrations. But the repeated freeze or thaw cycles of this kind of storage wreaked havoc on solubility and chemical stability causing the loss of countless compounds throughout industry.
Combinatorial chemistry as described above, fraught with problems of expense, purity, compound identification, and storage have largely been supplanted in the modern medicinal chemistry laboratory by the more measured and reliable techniques broadly termed "parallel synthesis."
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