Dynamic combinatorial chemistry

By modern definition, dynamic combinatorial chemistry is generally considered to be a method of facilitating the generation of new chemical species by the reversible linkage of simple building blocks, under thermodynamic control. Although this approach was arguably utilised in the work of Fischer and Werner as early as the 19th century, their respective studies of carbohydrate and coordination chemistry were restricted to rudimentary speculation, requiring the rationale of modern thermodynamics. It was not until supramolecular chemistry revealed early concepts of molecular recognition, complementarity and self-organisation that chemists could begin to employ strategies for the rational design and synthesis of macromolecular targets. The concept of template synthesis was further developed and rationalised through the pioneering work of Busch in the 1960s, which clearly defined the role of a metal ion template in stabilising the desired ‘thermodynamic’ product, allowing for its isolation from the complex equilibrating mixture. Although the work of Busch helped to establish the template method as a powerful synthetic route to stable macrocyclic structures, this approach remained exclusively within the domain of inorganic chemistry until the early 1990s, when Sanders et al. first proposed the concept of dynamic combinatorial chemistry. Early work by Sanders et al. employed transesterification to generate dynamic combinatorial libraries. In retrospect, it was unfortunate that esters were selected for mediating component exchange, as transesterification processes are inherently slow and require vigorous anhydrous conditions. However, their subsequent investigations identified that both the disulfide and hydrazone covalent bonds exhibit effective component exchange processes and so present a reliable means of generating dynamic combinatorial libraries capable of thermodynamic templation. This chemistry now forms the basis of much research in the developing field of dynamic covalent chemistry, and has in recent years emerged as a powerful tool for the discovery of molecular receptors. ==Protein-directed==

One of the key developments within the field of DCC is the use of proteins (or other biological macromolecules, such as nucleic acids) to influence the evolution and generation of components within a DCL. Protein-directed DCC provides a way to generate, identify and rank novel protein ligands, and therefore have huge potential in the areas of enzyme inhibition and drug discovery. Reversible covalent reactions The development of Protein-directed DCC has not been straightforward because the reversible reactions employed must occur in aqueous solution at biological pH and temperature, and the components of the DCL must be compatible with proteins. diselenides-disulfides exchange, disulphide formation, hemithiolacetal formation, hydrazone formation, imine formation and thiol-enone exchange. Pre-equilibrated DCL For reversible reactions that do not occur in aqueous buffers, the pre-equilibrated DCC approach can be used. The DCL was initially generated (or pre-equilibrated) in organic solvent, and then diluted into aqueous buffer containing the protein target for selection. Organic based reversible reactions, including Diels-Alder and alkene cross metathesis reactions, have been proposed or applied to Protein-directed DCC using this method. Reversible non-covalent reactions Reversible non-covalent reactions, such as metal-ligand coordination, has also been applied in Protein-directed DCC. This strategy is useful for the investigation of the optimal ligand stereochemistry at the binding site of the target protein. Enzyme-catalysed reversible reactions Enzyme-catalysed reversible reactions, such as protease-catalysed amide bond formation/hydrolysis reactions and the aldolase-catalysed aldol reactions, have also been applied to Protein-directed DCC. Analytical methods Protein-directed DCC system must be amenable to efficient screening. Multi-protein approach Although most applications of Protein-directed DCC to date involved the use of single protein in the DCL, it is possible to identify protein ligands by using multiple proteins simultaneously, as long as a suitable analytical technique is available to detect the protein species that interact with the DCL components. This approach may be used to identify specific inhibitors or broad-spectrum enzyme inhibitors. == Other applications ==

DCC is useful in identifying molecules with unusual binding properties, and provides synthetic routes to complex molecules that aren't easily accessible by other means. These include smart materials, foldamers, self-assembling molecules with interlocking architectures and new soft materials. Recently, DCC was also used to study the abiotic origins of life. ==See also==