Chemistry, combinatorial

Combinatorial chemistry is a rapidly expanding field that is particularly prominent in drug discovery and high-performance materials. It carries high hopes, but the number of commercial successes has been modest so far. 

Combinatorial chemistry began with the work of Bruce Merrifield in 1963 to develop a solid-phase peptide synthesizer machine, which was recognized by the awarding of the Nobel Prize in Chemistry in 1984. All proteins are linear sequences 

Then he removed the protection on the IINH2 end of the dipeptide amino and reacted with a solution of the third amino acid that was protected on the amino end. This sequence of steps was repeated for as many times as needed to make a protein with many amino acid sequences. 

Modern combinatorial chemistry involves a number of steps that begin with the creation of a library of molecules that are closely related in structure. The library can be created in two ways (a) parallel synthesis, which is simultaneous synthesis of numerous products in separate discrete reaction vessels (b) combinatorial synthesis, of numerous reactions within one single reaction vessel followed by separations. The initial successes in parallel synthesis have been in solid peptide synthesis of proteins, which was based on Merrifield s solid-phase peptide synthesis. 

The mix-and-split method was a combinatorial synthesis pioneered by Furka in 1988. The method is illustrated in figure 7.4 with three reaction vessels, each of which contains large quantities of small resin beads. The first vessel is treated with amino acid A to start a peptide, the second vessel with B, and the third vessel with C. Then the beads from the three vessels are mixed together and divided equally into three vessels. In the second generation of processing, the first vessel is treated with amino acid D, the second vessel with E, and the third vessel with F. Now we have a library 

The problems with combinatorial chemistry are twofold monkeys cost money and their output must be screened for relevancy. Has Hamlet been written  

To achieve reasonable cost, both the synthesis and analysis steps must be done at a small scale. The milliliter scale is now the state of the art but still smaller scales will become possible. See Chapter 16. For the moment, small shaker flasks and microtiter plates can be used to screen hundreds of experiments. Once tentatively identified at the small scale, the chosen molecule or cell line must be made in sufficient quantities 

The basic concept of combinatorial chemistry is best illustrated by an example. Consider, the reaction of a set of three compounds (Ax 3) with a set of three building blocks (Bi 3). In combinatorial synthesis, Ai would simultaneously 

Fundamentals of Medicinal Chemistry, Edited by Gareth Thomas 

The reactions used at each stage in such a synthesis normally involve the same functional groups, that is, the same type of reaction occurs in each case. Very few libraries have been constructed where different types of reaction are involved in the same stage. In theory this approach results in the formation of all the possible products that could be formed. However, in practice some reactions may not occur. 

The number of irreversible reactions used in the formation of synthetically useful covalent bonds largely outweighs that of reversible ones. Yet, the last period has witnessed a renewal of interest in the use of reversible reactions for synthetic purpose, thanks to the birth of dynamic combinatorial 

A number of reversible reactions leading to covalent connections between reactants such as olefin metathesis, imine and hydrazone formation, transesterification, thiol-disulphide interchange, transacetalation and so on have been employed in DCC. 

Since most of the DLs described in the Hterature consist of interconverting linear and cychc species, a deep knowledge of the mles governing macrocyclization under thermodynamic control is crucial to a quantitative analysis of the phenomenology related to DCC. Concepts and results described in Section 3.1 have to be taken into account when a DL is examined in quantitative terms. 

A very early example of DL generated under full thermodynamic control is due to Kawakami who described the ROP (Ring Opening Polymerization) of the series of formals (acetals of formaldehyde) depicted in Chart 1. 

For each series pC-CF-Y) , the distribution of products at equilibrium was measured at increasing initial monomer concentration [X-CF-Y]o, and a perfect adherence with theoretical prediction was verified in all cases. As an example, the original plot with data related to formal metathesis of 17-CF-6 is reported in Fig. 7. 

FIGURE 9.20 Privileged structures (9.35,9.38, and 9.41) with specific examples 

To match the incredible diversity of molecular space, pharmaceutical companies often rely on combinatorial chemistry. Combinatorial chemistry, or less formally combi chem or even just combi, is a technique for synthesizing large numbers of different molecules 

SCHEME 9.4 A simple synthetic scheme for combinatorial chemistry 

There are many variations of combinatorial chemistry, and all have distinct advantages and disadvantages. A comprehensive description of the different techniques is beyond the scope of this chapter. In the following sections, a few examples will highlight the main features common to most combinatorial approaches to library synthesis. This section contains a considerable amount of synthetic chemistry. The goal of this section is not to teach organic synthesis but instead to demonstrate the basics of chemical library synthesis. Do not get lost in the synthesis Focus instead on the characteristics and qualities specific to each combinatorial technique. 

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Compounds are transformed into each other by chemical reactions that can be run under a variety of conditions from gas-phase reactions in refineries that produce basic chemicals on a large scale, through parallel transformations of sets of compounds on well-plates in combinatorial chemistry, all the way to the transformation of a substrate by an enzyme in a biochemical pathway. This wide range of reaction conditions underlines the complicated task of imderstanding and predicting chemical reaction events. 

Mixtures containing up to several thousand distinct chemical entities are often synthesized and tested in mix-and-split combinatorial chemistry. The descriptor representation of a mixture may be approximated as the descriptor average of its individual component molecules, e.g., using atom-pair and topological torsion descriptors. 

Thus, in the area of combinatorial chemistry, many compounds are produced in short time ranges, and their structures have to be confirmed by analytical methods. A high degree of automation is required, which has fueled the development of software that can predict NMR spectra starting from the chemical structure, and that calculates measures of similarity between simulated and experimental spectra. These tools are obviously also of great importance to chemists working with just a few compounds at a time, using NMR spectroscopy for structure confirmation. 

Nowadays a broad range of methods is available in the field of chemoinfor-matics. These methods will have a growing impact on drug design. In particular, the discovery of new lead structures and their optimization will profit by virtual saeening [17, 66, 100-103]. The huge amounts of data produced by HTS and combinatorial chemistry enforce the use of database and data mining techniques. 

Combinatorial chemistry has significantly increased the nurnjjers of molecules that can be synthesised in a modern chemical laboratory. The classic approach to combinatorial synthesis involves the use of a solid support (e.g. polystyrene beads) together with a scheme called split-mix. Solid-phase chemistry is particularly appealing because it permits excess reagent to be used, so ensuring that the reaction proceeds to completion. The excess... 

Martin E J, D C Spellmeyer, R E Critchlow Jr and J M. Blaney 1997. Does Combinatorial Chemistry Obviate Computer-Aided Drug Design In Lipkowitz K B and D B Boyd (Editors) Reviews in Computational Chemistry Volume 10. New York, VCH Publishers, pp. 75-100. 

Chemometrics. Statistics and Computer Application in Analytical Chemistry. New York, Wiley-VCH. yer D C and P D J Grootenhuis 1999. Recent Developments in Molecular Diversity nputational Approaches to Combinatorial Chemistry. Annual Reports in Medicinal Chemistry 187-296,... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

The second method for mixture analysis is the use of specialized software together with spectral databases. We have developed a mixture analysis program AMIX for one- and multidimensional spectra. The most important present applications are the field of combinatorial chemistry and toxicity screening of medical preparations in the pharmaceutical industry. An important medical application is screening of newborn infants for inborn metabolic errors. 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

H. Wennemers, Combinatorial chemistry A tool for the discovery of new catalysts. Comb Chem High Throughput Screening 4 273-285 2001. 

Chapters 1 and 2 have been reorganised and updated in line with recent developments. A new chapter on the Future of Purification has been added. It outlines developments in syntheses on solid supports, combinatorial chemistry as well as the use of ionic liquids for chemical reactions and reactions in fluorous media. These technologies are becoming increasingly useful and popular so much so that many future commercially available substances will most probably be prepared using these procedures. Consequently, a knowledge of their basic principles will be helpful in many purification methods of the future. 

WA WaiT. Combinatorial chemistry and molecular diversity. An overview. J Chem Inf Comput Sci 37 134-140, 1997. 

EK Kick, DC Roe, AG Skillman, G Lm, TJ Ewing, Y Sun, ID Kuntz, lA Ellman. Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsm D. Chem Biol 4(4) 297-307, 1997. 

A Polmski, RD Eemstem, S Shi, A Kuki. LiBrain Software for automated design of exploratory and targeted combinatorial libraries. In IM Chaiken, KD Janda, eds. Molecular Diversity and Combinatorial Chemistry Libraries and Drug Discovery. ACS Conf Proc Ser. Washington, DC Am Chem Soc, 1996, pp 219-232. 

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