ABSTRACT
The different approaches to the synthesis of libraries illustrate the different philosophies of laboratories and companies. The same difference in thinking can be found in the value given to the purity of prepared compounds. Different companies apply different criteria. However, in the end you will always hear: “We do not accept anything worse than 80 (75, 85, 70)% purity.” Well, what purity is being talked about? High-performance liquid chromatography with ultraviolet detector? All compounds would have to have the same absorbtion coefficient. Or evaporative light-scattering (ELS) detector? Slightly better. Or mass spectroscopic (MS) purity? There is nothing like MS purity! Maybe nuclear magnetic resonance (NMR), but who can evaluate several hundreds or thousands of NMR spectra each day? Anyway, what does this number tell you? Only a rough approximation of how many potentially good leads you will miss by not looking at the samples at all. The only really important information that the chemist should provide to the biologist is whether he or she can guarantee the preparation of the same sample tomorrow or a year from now. Does he or she have the stable, well-rehearsed protocol and reliable source of starting materials? If yes, every biologist should be happy to screen his or her compounds. If the biological activity is found in the impure sample, the likelihood that the active component of the mixture can be found after isolation of all components is pretty high. By the way, the probability that the activity is higher than observed in the mixture is also high. And, as a free bonus, the active species might not be the one that was targeted but rather the side product of unexpected (and hopefully novel) structure. This would make the patent people happy. For a long time I did not meet a combinatorial chemist who did not have a story about active compound being a side product.
