1. INTRODUCTION
Finding novel biologically active leads is a challenging process. Historically, the main source of biologically active compounds for used in drug discovery programmes has been natural products, isolated from plant, animal or fermentation sources.
Combinatorial chemistry is one of the important new methodologies developed by researchers in the pharmaceutical industry to reduce the time and costs associated with producing effective, and competitive new drugs. Combinatorial chemistry is used to create a large population of molecules - called libraries - that can be screened in one time.
The aim of combinatorial synthesis is the ability to generate large numbers of chemical compounds very quickly. This advantage has inspired many different uses, employing many variants of the technology such as solution or solid phase synthesis. Chemistry in the past has been characterised by slow, steady, and painstaking work; combinatorial chemistry has broken many of the preconceptions and permitted a level of chemical productivity undreamed of just ten years ago. By producing larger and more diverse compounds companies increase the chance to find more biologically active compounds.
Combinatorial chemistry has also initiated a reassessment of the traditional methods of organic synthesis.
1.1 Principle
Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules may be synthesised in a time and submitted for pharmacological assay. The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple methodology.
In the past chemists have traditionally made one compound at a time. For example compound A would have been reacted with compound B to give product AB, which would have been isolated after reaction work up and purification through crystallisation, distillation, or chromatography. In contrast to this approach, combinatorial chemistry offers the potential to make every combination of compound A1 to An with compound B1 to Bn. (Figure 1) The range of combinatorial techniques is highly diverse, and these products could be made individually in a parallel or in mixtures, using either solution or solid phase techniques. Whatever the technique used the common denominator is that productivity has been amplified beyond the levels that have been routine for the last hundred years.
1.2 Combinatorial Libraries
It is widely accepted that combinatorial chemistry "was born" in the early 1980s when Mario Geysen, then in Melbourne, Australia, invented the pin method in which simultaneous synthesis of diversified peptides gave rise to the first combinatorial libraries.(1)
The use of Combinatorial Chemistry synthetic methods allows a very large number of molecules to be synthesised much more rapidly and at lower cost than traditional synthetic chemistry.
Combinatorial Chemistry libraries are usually represented by one or more structures with a small number of R-group positions. For each R-group position there are lists of alternative groups.
The aim of Library Design is to reduce the number of molecules, which need to be made without decreasing the diversity of the library. This has the potential of finding leads more rapidly because a smaller number of molecules are tested by avoiding molecules which are very similar.
1 Geysen, H.M. et al. 1986. Molecular Immunology, 23. 709 - 715.