Combinatorial chemistry, small

Combinatorial chemistry (Section 27.18) A method for carrying out a large number of reactions on a small scale in the solid phase so as to generate a library of related compounds for further study, such as biological testing. 

Small-diameter packed columns offer (17) the substantial advantages of small volumetric flow rates (1-20 (p.L min )), which have environmental advantages, as well as permitting the use of exotic or expensive mobile phases. Peak volumes are reduced (see Table 1.1), driven by the necessity of analysing the very small (pico-mole) amounts of substance available, for example, in small volumes of body fluids, or in the products of single-bead combinatorial chemistry. 

Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to tfie different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

Precisely defined collections of different chemical compounds are denominated as chemical libraries that can be efficiently prepared by methods of combinatorial chemistry. Each chemical compound owes specific structural, steiic, and electronic properties that determine all possible interactions of the small molecule with a given protein or receptor. The molecule s properties are based on the steiic arrangement of functional groups, including the conformations that can be attained by a specific structure. 

Tietze, L.F. Lieb, M.E. (1998) Domino Reactions for Library Synthesis of Small Molecules in Combinatorial Chemistry. Current Opinion in Chemical Biology, 2, 363-371. 

The development of protein chip assays to determine protein function using purified components is a rapidly advancing area. Automated systems for the assay of protein function on chips in parallel for thousands of proteins simultaneously will likely be available in the next few years. These miniaturized arrays will be useful for basic research as well as for diagnostics and drug development. For instance, the combination of protein chips with combinatorial chemistry will allow the simultaneous screening of vast collections of small molecules against vast collections of potential target proteins. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

CombiCHEM System (Fig. 3.9) For small-scale combinatorial chemistry applications, this barrel-type rotor is available. It can hold two 24- to 96-well microtiter plates utilizing glass vials (0.5-4 mL) at up to 4 bar at 150 °C. The plates are made of Weflon (graphite-doped Teflon) to ensure uniform heating and are sealed by an inert membrane sheet. Axial rotation of the rotor tumbles the microwell plates to admix the individual samples. Temperature measurement is achieved by means of a fiber-optic probe immersed in the center of the rotor. 

Keywords Combinatorial Chemistry m Solid-Phase Synthesis m Solid-Phase Scavenger m Linker m Targeted Library m Small Molecule Libraries... 

The identification of compounds with a desired property is a central pursuit in science. In the field of drug discovery combinatorial chemistry has played an increasingly important role for identification and optimization of drug leads which target therapeutically important biomolecules. For the successful implementation of combinatorial methods, new and innovative synthesis methods have been developed. Additionally, novel conceptual approaches to the design of compounds have been pursued to more efficiently generate libraries of small molecules. 

Combinatorial approaches to the synthesis of libraries of peptides, nucleotides, and many classes of small organic molecules are well documented.35 However, the field of oligosaccharide combinatorial chemistry is still in its infancy.36 The slow development is due to the inherent complexities in the synthesis of oligosaccharides. 

Hermkens, P.H.H. and Muller, G., The impact of combinatorial chemistry on drug discovery, in Ernst Schering Research Foundation Workshop Small Molecule-Protein Interactions, Vol. 42, 2003, pp. 201-220. 

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