Combinatorial chemistry mixtures

Since the relatively high concentration of each component required by NMR adds up to a high total concentration of compounds for the mixture, the application of this methodology to screen combinatorial chemistry mixtures for biological activity will likely be limited by the total compound concentration tolerated by the biological target. Nevertheless, this NMR method, when applied to suitable systems, should add a powerful tool for mixture analysis. 

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. 

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. 

Houghten RA. Parallel array and mixture-based synthetic combinatorial chemistry tools for the next millennium. 

In addition, SPOS can easily be automated using appropriate robotics for both filtration and evaporation of the volatiles from the reaction mixture to obtain the cleaved product. Furthermore, SPOS can be applied to the powerful split-and-mix strategy, which has proved to be an important tool in combinatorial chemistry [7]. 

Immobilized catalysts on solid supports inherently have benefits because of their easy separation from the products and the possibility of recycling. They are also expected to be useful for combinatorial chemistry and high-throughput experimentation. The polystyrene-bound BINAP/DPEN-Ru complex (beads) in the presence of (CH3)3COK catalyzes the hydrogenation of l -acetonaphthone with an SCR of 12 300 in a 2-propanol-DMF mixture (1 1, v/v) to afford the chiral alcohol in 97% ee (Fig. 32.35) [113]. This supported complex is separable... 

This chapter will cover the efforts that have been made to use the principles of combinatorial chemistry in the development of new catalysts. In the last few years there has been a lively discussion of what is the correct definition of combinatorial chemistry. Some workers reserve the term combinatorial chemistry for the synthesis and evaluation of mixtures. For the purpose of this chapter, we will employ a liberal interpretation of the term. Since one of the definitions of the word combinatorial is, of or involving combinations (14), we will use the term to include what may be referred to as parallel synthesis. In parallel synthesis, one generates a combination of molecules, be they in separate vials or on separate pins. One view may be that a collection of vessels represents a combination of molecules. It is for this... 

Combinatorial chemistry has been used with great success to create libraries in the development of inhibitors in the field of peptide and nucleic acid recognition.5,6 The basic strategy of a library approach is to synthesize large sets of molecules at a time, even as complex mixtures, and then determine whether any of the compounds is inhibitory. The active compound must be subsequently identified. This strategy stands in contrast to the extremely laborious and expensive process of traditional medicinal chemistry, where individual molecules are carefully synthesized and evaluated. The... 

Classical Drug Discovery focused on the biological evaluation of individual purified compounds. But in light of HTS and combinatorial chemistry, it became widely accepted that the biological screening of mixtures of compounds should, in theory, provide much more biological data in the same amount of time used for bioassay of individual compounds,... 

While this may in fact be the case for natural product mixtures, it is rarely the case when dealing with synthesized mixtures. Despite our attempts to create real molecular diversity in the test tube, our efforts have not even begun to anticipate the true diversity of atomic connectivity within "drug space" (estimated to be of the order of 1063 unique compounds, theory, famously in this case, greatly outpacing the amount of matter in the universe). Thus, combinatorial chemistry was never practically able to produce true chemical diversity and compounds produced in such library format ended up looking very much like one another, with the attendant similarities in biological activity profiles. 

Houghten, R.A., Parallel array and mixture-based synthetic combinatorial chemistry tools for the next millennium, Anna. Rev. Pharmacol. Toxicol., 2000, 40, 273-282. 

The use of combinatorial chemistry to produce libraries of compounds is pivotal in drug discovery. Screen hits need to be analyzed to identify the structure of the individual active component. Large numbers of samples containing only small quantities of complex mixtures require... 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

The ALIS quench method for dissociation rate measurement uses little protein and requires no biochemical assay for its implementation, yet the method readily yields quantitative values for the dissociation rates of the protein-ligand complexes. The technique can be used with pools of ligands to provide a quantitative rank ordering of the dissociation rates of all the components of the mixture. Since it is not necessary to know the exact concentrations of the ligands under study, the dissociation rate assessment can be performed using impure compounds, such as unpurified compound mixtures derived from combinatorial chemistry synthesis. The method does not require a foreknowledge of active protein concentration to measure and rank ligands based on their rates of dissociation. As such, the technique is self-contained and does not rely upon an external measure of protein activity as one of its input parameters. 

Most important of all, however, is the possibility of running the Merrifield procedure on any number of resin beads (or other support systems) simultaneously in a number of reaction chambers. An example of this alternative is the so-called split and mix system of combinatorial chemistry. The first step in this kind of system is to prepare some number of monomer-support units (three in the example shown below), in which the monomer present differs from chamber to chamber. In the diagram below, the units are represented as -X, -Y, and -Z. These three units are washed and then mixed with each other in a single container. The mixture is then divided and placed into three separate containers. One of the most common containers used contains a number of wells in a plastic or glass dish that are miniature versions of the common petri dish used in biology experiments. 

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