Combinatorial chemistry library, quality

To assess the quality of a combinatorial chemistry library, it is essential to determine the purity and quantity of the expected products. Commercial software, developed by instrument manufacturers, has made possible the unattended and rapid analysis of tens of thousands of individual components of a specific library. The application of LC/MS in high-throughput screening of combinatorial libraries has been reviewed by several authors [72-78]. 

As the nature of chemistry space depends upon the way in which compounds are represented, an absolute or universal chemistry space does not exist. Thus, any procedure that utilizes chemistry space may be subject to considerable uncertainty, and the results obtained in different chemistry spaces are likely to differ, sometimes in quite significant ways. This rather daunting circumstance has necessitated the use of practical, heuristic approaches that, while imperfect, have nevertheless performed in a reasonably satisfactory manner over the last three years. During this period about 120000 diverse, quality compounds have been added to our corporate compound collection. This does not include the many compounds obtained from combinatorially derived libraries and special target-directed (e.g., kinase) libraries. 

There are many variations of combinatorial chemistry, and all have distinct advantages and disadvantages. A comprehensive description of the different techniques is beyond the scope of this chapter. In the following sections, a few examples will highlight the main features common to most combinatorial approaches to library synthesis. This section contains a considerable amount of synthetic chemistry. The goal of this section is not to teach organic synthesis but instead to demonstrate the basics of chemical library synthesis. Do not get lost in the synthesis Focus instead on the characteristics and qualities specific to each combinatorial technique. 

Lead optimization Combinatorial/medicinal chemistry support Open access Purification Combinatorial mixtures Combinatorial libraries-quality control Taylor et al., 1995 Pullen et al., 1995 Zeng and Kassel, 1998 Zeng et al., 1998 Richmond et al., 1999 Yates et al., 2001 Dunayevskiy et al., 1995 Fang et al., 1998 Fitch 1998-1999 FIsu et al., 1999 Dulery et al., 1999 Ventura et al., 2000 Shah et al., 2000... 

This first section focuses on three major areas library generation method (mixtures and single compounds) chemistry (solid-phase and solution synthesis) and quality/speed (analytical and automation). Finally, the section ends with a chapter reviewing examples where combinatorial chemistry/rapid organic synthesis has been used for discovering novel lead structures for pharmaceutical purposes. 

However, this assertion is based on the assumption that the compounds intended to be made were actually made in sufficient quantities and to adequate levels of purity. The yields in many Combinatorial Chemistry synthesis vary significantly and the purity may also be problematic. The additional steps required to purify and measure the quantity generated are not usually necessary to establish whether the major product shows any significant biological activity. It is therefore not surprising that many companies perform quality control checks on a subset oftheir samples. This prohibits accurate decisions on the overlap of libraries. 

In addition to quality control over compound collections, the issue of purity of synthetic libraries derived using combinatorial chemistry quickly came under the microscope. In the early to mid-1990s, combichem became a household word throughout the pharmaceutical industry and was believed to be a key technology that would revolutionize drug discovery. The basis of... 

A very important use of MS in combinatorial chemistry is in quality control of combinatorial libraries. As much as possible, we would like to have pure compounds generated in high yield, with no side reactions or by-products. We also need to verify that every component actually exists in a library (i.c.. that no reactions failed). Only MS provides the sensitivity and versatility to perform this checking with both solid-pha.se and solution-phase libraries... 

For a recent review of analytical methods used for the quality control of combinatorial libraries, see WL Fitch. Analytical methods for the quality control of combinatorial libraries. In W Moos, M Pavia, B Kay, A Ellington, eds. Annual Reports in Combinatorial Chemistry and Molecular Diversity, Vol. 1. Leiden, The Netherlands ESCOM, 1997, pp 59-68. 

Yan B, Fang L, Irving M, Zhang S, Boldi AM, Woolard F, Johnson CR, Kshirsagar T, Figliozzi CM, Krueger CA, and Collins N. Quality Control in Combinatorial Chemistry Determination of the Quantity, Purity, and Quantitative Purity of Compounds in Combinatorial Libraries. / Com Chem 2003 5 547-559. 

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