Combinatorial chemistry “combichem

Two distinct strategies of peptide lihrary preparation are commonly used parallel synthesis and so-called sptit-and-mix chemistry (also known as divide-couple- ecom-bine, portion-mixing and split-pool synthesis). Both are often described as combinatorial chemistry (combichem), although this is only strictly true for sptit-and-mix synthesis. Parallel synthesis is simply the preparation of many batches of peptide at the same time in separate parallel channels of one or more machines. In the case of library synthesis, the amino acid sequence is systematically varied between channels. Commonly this allows the synthesis of several hundred different sequences at the same time. It has the advantages that larger amounts are usually prepared than in split-and-mix, and that one can easily tell what sequence of residues was used in any potential hit. 

CombiCHEM System (Fig. 3.9) For small-scale combinatorial chemistry applications, this barrel-type rotor is available. It can hold two 24- to 96-well microtiter plates utilizing glass vials (0.5-4 mL) at up to 4 bar at 150 °C. The plates are made of Weflon (graphite-doped Teflon) to ensure uniform heating and are sealed by an inert membrane sheet. Axial rotation of the rotor tumbles the microwell plates to admix the individual samples. Temperature measurement is achieved by means of a fiber-optic probe immersed in the center of the rotor. 

Davies, K., Briant, C. Combinatorial chemistry library design using pharmacophore diversity, http //www.netsci.org/ Science / Combichem/feature05. html. 

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. 

Davies, E.K. and Briant, C. Combinatorial Chemistry Library Design Using Pharmacophore Diversity. Accessible through URL http //www.awod.com/netsci/Science/Combichem/feature05.html. 

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... 

Mjalli, A. M. M. and Toyonaga, B. E. (1995) Solid support combinatorial chemistry in lead discovery and SAR optimization http //www.netsci.org/Science/ Combichem/feature03.html. Net. Sci. 1. 

Borman, S. Rescuing combichem. Diversity-oriented synthesis (DOS) aims to pick up where traditional combinatorial chemistry left off. Chem. Eng. News 2004, S2(40), 32-40. 

Preparation of catalyst libraries for the discovery phase can be broadly divided into two categories (1) solution-based methods, and (2) thin-film deposition/based methods. The solution-based methods include those that utilize (1) multi-tasking robotic workstations [14-16] (2) inkjet printhead technology [17], and (3) microjet technology [18]. The thin-film deposition-based methods employ electron beam and thermal evtqroration, sputtering, pulsed laser ablation, and chemical vapor deposition (see [60] in [13] for a list of references). A detailed discussion of how these have been applied is provided elsewhere [13]. Web sites provide links to various aspects of combinatorial chemistry (www.combichem.net and www.5z.com). Here, the hardware aspects are lightly sketched. 

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