Biological Problems Chemical Synthesis

The study of the biosynthesis of vitamin B 2 is a saga whose resolution, due primarily to Battersby (80—83) and Scott (84,85), requited an effort on the same magnitude as the total synthesis. It was only when recent molecular biology tools became available to complement en2ymology, isotopic labeling, chemical synthesis, and spectroscopy that solution of this problem became possible. 

When compared to traditional chemical synthesis, processes based on biocatalysts are generally less reliable. This is due, in part, to the fact that biological systems are inherently complex. In bioprocesses involving whole cells, it is essential to use the same strain from the same culture collection to minimise problems of reproducibility. If cell free enzymes are used the reliability can depend on the purity of the enzyme preparation, for example iso-enzyme composition or the presence of other proteins. It is, therefore, important to consider the commercial source of the enzyme and the precise specifications of the biocatalyst employed. 

Although combinatorial chemistry and HTS have offered medicinal chemists a much broader range of possibilities for lead discovery and optimization, the number of chemical compounds that can be reasonably synthesized, which is sometimes called virtual chemistry space , is stiU far beyond today s capability of chemical synthesis and biological assay. Therefore, medicinal chemists continue to face the same problem as before which compounds should be chosen for the next round of synthesis and testing For chemoinformaticians, the task is to develop and utilize various computer programs to evaluate a very large number of chemical compounds and recommend the most promising ones for bench medicinal chemists. This process can be called virtual... 

It is of some interest to note that 24 of the starting fragments were prepared by solid-phase methods in order to simplify and accelerate the synthesis. This confirms what we have believed for a long time, i.e. that the various approaches (chemical, enzymatic, and biological) to the synthesis of peptides and proteins are not mutually exclusive but, rather, they can complement one another when judiciously selected for the particular problem at hand. 

The recent revolution in molecular biology has brought with it an increased demand for the efficient chemical synthesis of short DNA segments, called oligonucleotides. The problems of DNA synthesis are similar to those of protein synthesis (Section 26.10) but are more difficult because of the complexity of the nucleotide monomers. Each nucleotide has multiple reactive sites that must be selectively protected and deprotected at the proper times, and coupling of the four nucleotides must be carried out in the proper sequence. Automated DNA synthesizers are now available, however, that allow the fast and reliable synthesis of DNA segments up to 200 nucleotides in length. 

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