Synthesis split-and-mix

The solid-phase technique of split and mix synthesis relies on the efficiency of mixture-based synthesis to provide very large libraries (millions) of discrete compounds (Figure 4).[161 In this approach, each resin bead is treated with a single building block for each synthesis step. Thus any single resin bead possesses identical copies of one library member, but the identity of the library member on any bead is lost due to the mix step of the process. Elegant strategies have been developed to chemically encode the syn-... 

Combinatorial chemistry is the production of libraries of compounds that represent permutations of a set of chemical variables. These variables include the nature of the substituent in a particular molecule, both in type and size, changes in the components in a mixture of materials, e.g. in ceramics and changes in process parameters, e.g. temperature, pH etc. Chemical libraries are usually created by one of two methods split and mix or parallel synthesis . Split and mix synthesis is used to produce small quantities of a relatively large number of compounds and requires assays to be performed on pools of compounds. Parallel synthesis is used to produce libraries... 

In the split-mix synthesis, like in other solid phase procedures, the beads behave very much like tiny reaction vessels, which do not interchange their contents with the other ones. Each of the millions of these reaction vessels preserves its content until the end of the synthesis, when they become containers of a single substance. If peptides are produced, their identity can be determined by automatic sequencing [9], It is sufficient to sacrifice a fraction of the total quantity for this purpose. All this means that the split-mix synthesis is, in fact, a parallel procedure, with unprecedented efficiency, however, leading to individual compounds. This feature of the split and mix synthesis allows screening the products in three different ways ... 

Almost all of the analytical characterization tools (e.g., HPLC, NMR, FTIR, and LC/MS) are serial-based techniques, and parallel synthesis is inherently parallel. Consequently, this led rapidly to a new bottleneck in the discovery process (i.e., the analysis and purification of compound libraries). Parallel synthesis suffers from some of the same shortcomings of split and mix synthesis (e.g., the expected compound may not be pure, or even synthesized in suffi-... 

Figure 3-3 Split-and-mix synthesis of tripeptides In the first step, all the beads in a given container have a single monopeptide. These are all mixed together, then split into three aliquots and re-treated, attaching a second peptide. After just one more step, all 27 possible combinations exist, spread among the three containers.

Currently available solid-phase synthesis reaction blocks with microtiter plate and other footprints are listed in Table 1. Larger footprints allow higher reaction volumes (J-Kem). The CSPS Multiblock offers a simple means of performing split-and-mix synthesis. 

Special features/comments glass cover for randomization of resin (split-and-mix synthesis) available reflux option block for collection of products available concentrator cover for evaporation from collection block available ... 

Particles can be analysed in microfluidic systems, providing a high throughput platform, which can be integrated into low-cost devices for biochemical research and point-of-care medical diagnostic applications [9,10]. Potentially particles could be directed post analysis into different reaction vessels, for split-and-mix synthesis where molecules such as a peptides or oligonucleotides are progressively and combina-torially synthesized on the beads [11]. 

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