Library of compounds

One application of clustering could, for example, be the comparison of compound libraries A training set is chosen which contains members of both libraries. After the structures are coded (cf. Chapter 8), a Kohonen network (cf. Section 9.5.3) is trained and arranges the structures within the Kohonen map in relation to their structural similarity. Thus, the overlap between the two different libraries of compounds can be determined. 

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. 

A new solid phase method to synthesize libraries of compounds based on 1,2,5-thiadiazolidine heterocycle was developed (00TL(41)3161). Starting from the coupling of the protected aminoacid to the resine functionalized with p-alkoxybenzylalcohol as the linker, a series of sulfahydantoins 251 could be obtained. The method is applicable to aminoacids with a basic side chain, aliphatic aldehydes or aldehydes with basic functionalities. 

The screening of libraries of compounds for the desired property constitutes an essential part of the combinatorial process. The easier and the faster the screening, the higher the throughput and the more compounds can be screened in a unit of time. This paradigm has led Still s group to develop a combinatorial approach to chiral selectors that involves a visual screening step by optical microscopy that enables the manual selection of the best candidates [81]. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

The question of selecting the most appropriate method for any one compound has been addressed recently by Kiihne et al. [52]. Initially several different methods are used to predict the solubility of a reference library of compounds. A subset of compounds from this reference library that are most similar to the compound of interest is identified and the method with the smallest sum of errors in the predicted solubility for this subset is chosen to predict the solubility. Dearden [3] considered whether a consensus approach could improve prediction over any one method. While the predictions from certain pairs of methods could be combined with improved results, some combinations led to poorer performance than either method alone. Chen et al. [53] were able to achieve improved correlation with their QSPR model using different QSPRs for different classes of compounds. Thus, while each QSPR used the same set of eight descriptors, the contribution of each descriptor changed according to the compound type. Each group had 82-101 compounds and achieved an of 0.86-0.92. 

The objective of traditional multistep synthesis is the preparation of a single pure compound, but combinatorial synthesis is designed to make many related molecules.57 The purpose is often to have a large collection (library) of compounds for evaluation of biological activity. A goal of combinatorial synthesis is structural diversity, that is, systematic variation in subunits and substituents so as to explore the effect of a range of structural entities. In this section, we consider examples of the application of combinatorial methods to several kinds of compounds. 

In a sense, Flow NMR is like HPLC-NMR without the chromatography part. It has found use in the field of array chemistry where libraries of compounds, usually with a common motif, are made - or at least presented - in the wells of a plate. ... 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

In a serial mode (Fig. 36.1), one experimental step (in catalysis research this is usually the preparation of the ligand or the catalyst) is repeated n times before moving on to the next step. The only difference with traditional research is that the complete experiment (synfhesis/testing/analysis) is carried out for a set of catalysts rather than for an individual species. For example, a library of ligands from the same class can be assembled via traditional organic synthesis prior to its testing in catalysis. (A library of compounds is a rather large collection of different compounds with some common features and usually the same function, for example triarylphosphines or imidazolidinones.) Ideally, the compounds in the library can be structurally varied in at least two positions to ere-... 

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

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