Combinatorial techniques

Some particular features of the analysis of products obtained by combinatorial methods have impaired the use of NMR spectroscopy in the initial phase of the development of this technique. Combinatorial chemistry produces large number of compounds in a very short period of time, in small quantities and instead of using traditional glassware for synthesis employs 96-well microtiter plates to store, transport and sometimes even to synthesize the compounds of interest. Another issue is the need to characterize solution and solid samples, since solid phase synthesis is extensively used in combichem. In this context, the need of an efficient and universal sample analysis remains a challenge. Actually, most combichem programs obtain mass spectrometry and UV (photodiode-array detection) data on their samples but clearly the use of NMR spectroscopy provides a structural characterization unparalleled by the aforementioned techniques. In the last years an increasing number of new NMR methods opened the possibility for the utilization of this analytical technique for monitoring combinatorial chemistry reactions. The first part of this chapter will focus on the recent developments introduced in NMR spectroscopy to overcome these difficulties. 

In the past 15 years, combined advances in computer technology and innovative algorithms development provided the possibility to perform complex computational operations in a reasonable time scale. Therefore these theoretical methods, when used together with modern experimental techniques (combinatorial chemistry and high-throughput screening), are now widely used. 

The method of generating functions is in concurrence with combinatorial methods and recursive techniques. Combinatorial methods have been used most early in particular by Flory and Stockmayer to derive critical branching [15],... 

Using these techniques (combinatorial biosynthesis) with streptomycetes, the polyketides have now been investigated, including not only the macrolides (e. g., erythromycin) but also polycyclic aromatic compounds (e.g., actinorhodin, tetracenomycins). The formation of hybrids can alter not only the size of the poly ketide skeleton, its stereochemistry or its functionality but also enzyme systems of the later steps of biosynthesis such as, e. g., oxygenases or glycosy Itrans-ferases. In practice major difficulties arise because each intermediate in the biosynthetic sequence is a substrate for the following enzyme thus if a changed substrate is not accepted by the respective enzyme the biosynthesis breaks down. 

It is worth noting that combinatorial chemistry has only been explored in the field of fuel cell electrocatalysis for a short time (around ten years). Therefore, it is still a developing and maturing technology. With improvement in both catalyst library preparation and screening techniques, combinatorial methods will become more important in new fuel cell electrocatalyst development. It is also believed that this combinatorial method will speed up new catalyst exploration, and thus accelerate developments toward PEM fuel cell breakthrough and commercialization. 

The basic scheme of this algorithm is similar to cell-to-cell mapping techniques [14] but differs substantially In one important aspect If applied to larger problems, a direct cell-to-cell approach quickly leads to tremendous computational effort. Only a proper exploitation of the multi-level structure of the subdivision algorithm (also for the eigenvalue problem) may allow for application to molecules of real chemical interest. But even this more sophisticated approach suffers from combinatorial explosion already for moderate size molecules. In a next stage of development [19] this restriction will be circumvented using certain hybrid Monte-Carlo methods. 

Nowadays a broad range of methods is available in the field of chemoinfor-matics. These methods will have a growing impact on drug design. In particular, the discovery of new lead structures and their optimization will profit by virtual saeening [17, 66, 100-103]. The huge amounts of data produced by HTS and combinatorial chemistry enforce the use of database and data mining techniques. 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

Combinatorial. Combinatorial methods express the synthesis problem as a traditional optimization problem which can only be solved using powerful techniques that have been known for some time. These may use total network cost direcdy as an objective function but do not exploit the special characteristics of heat-exchange networks in obtaining a solution. Much of the early work in heat-exchange network synthesis was based on exhaustive search or combinatorial development of networks. This work has not proven useful because for only a typical ten-process-stream example problem the alternative sets of feasible matches are cal.55 x 10 without stream spHtting. 

UNIQUAC is significant because it provides a means to estimate multicomponent interactions using no more than binary interaction experimental data, bond angles, and bond distances. There is an implicit assumption that the combinatorial portion of the model, ie, the size and shape effects, can be averaged over a molecule and that these can be directly related to molecular surface area and volume. This assumption can be found in many QSAR methods and probably makes a significant contribution to the generally low accuracy of many QSAR prediction techniques. 

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 methods are often referred to as in vitro or directed evolution techniques. In nature, the random DNA mutations that lead to changes in protein sequences occur rarely and so evolution is usually a slow... 

Ultramodern techniques are being applied to the study of corrosion thus a very recent initiative at Sandia Laboratories in America studied the corrosion of copper in air spiked with hydrogen sulphide by a form of combinatorial test, in which a protective coat of copper oxide was varied in thickness, and in parallel, the density of defects in the copper provoked by irradiation was also varied. Defects proved to be more influential than the thickness of the protective layer. This conclusion is valuable in preventing corrosion of copper conductors in advanced microcircuits. This set of experiments is typical of modern materials science, in that quite diverse themes... combinatorial methods, corrosion kinetics and irradiation damage... are simultaneously exploited. 

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