Libraries, in combinatorial chemistry

Felder E, Solid phase synthesis of organic libraries, in Combinatorial Chemistry and Combinatorial Technologies Methods and Applications (Eds. S. Miertus, G. Fassina), chapter 5 pp. 75-88, 2005, this volume. 

Hilaire, P.M.St. and Meldal, M., Glycopeptide and oligosaccharide libraries, in Combinatorial Chemistry Synthesis, Analysis, Screening, Jung, G., Ed., WUey-VCH, Weinheim, 1999, chap. 8. 

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. 

Combinatorial Chemistry. Figure 1 Whereas in classical chemical synthesis one target molecule was prepared in combinatorial chemistry the systematic combination of building blocks generates chemical libraries. 

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. 

Recently, a solid-phase synthesis was used iteratively for the synthesis of organic substances like oligocarbamates [13] and oligoureas [14] by repeated coupling to amino-functionalized supports. In this way substance libraries [15] have been developed showing that iterative methods can also be employed in combinatorial chemistry [16]. 

Kobayashi, S. Combinatorial Library Synthesis Using Polymer-supported Catalysts. In Combinatorial Chemistry, Fenniri, H., Ed., Oxford University Press Oxford, U.K., 2000 pp 421-432. 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

Pirrung, M.C., Chau, J.H.-L., and Chen, J., Indexed combinatorial libraries nonoligomeric chemical diversity for the discovery of novel enzyme inhibitors, in Combinatorial Chemistry, Wilson, S.R. and Czarnik, A.W., Eds., Wiley, New York, 1997, pp. 191-206. 

Carell, T., Wintner, E.A., Sutherland, A.J., Rebek, J. Jr, Dunayevskiy, Y.M., and VouROS, P. New promise in combinatorial chemistry synthesis, characterization, and screening of small-molecule libraries in solution. Chem. Biol. 1995, 2, 171-183. 

Other terms have been employed for this general concept, including self-assembled combinatorial libraries, constitutional dynamic chemistry, and virtual combinatorial libraries . Dynamic combinatorial chemistry and dynamic combinatorial library seem to have found the broadest usage, while virtual combinatorial library is perhaps best reserved for conditions under which library members form at concentrations below detection limits in the absence of target (e.g.. Reference 81). 

Mang C, Jakupovic S, Schunk S, Ambrosi H-D, Schwarz O, Jakupovic J. (2006) Natural products in combinatorial chemistry an andrographolide-based library. J Com Chem 8 268-274. 

The great advantage of this approach to synthesis is, of course, speed. Making the 200 compounds in the library just discussed by traditional methods would take a very long time, considerable money, and much labor. In fact, costs and time constraints would probably make the process prohibitive by traditional techniques. In combinatorial chemistry, however, the 200 compounds in the library can be made all at once with relatively little cost and expenditure of time and money. The only problem (and a significant problem it is ) is to find out which of the 200 compounds (if any) meet some predetermined criterion, such as biological potency. 

In fact, the distinction between solid-phase and solution-phase processes is largely of historical interest and does not necessarily describe the range of experiments now being carried out in combinatorial chemistry. Researchers are finding ways of using elements from both approaches through which a library of products can be synthesized and then purified and analyzed in the most effective manner possible. 

Sarko, C.R., Microwave-Accelerated Combinatorial Library Design and Development, ACS Prospectives Proceedings in Combinatorial Chemistry 2002, Leesburg, VA. 

Intelligent Design in Combinatorial Chemistry Use of Designed Peptide Libraries to Explore Secondary and Tertiary Structures in Peptides and Proteins... 

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