Parallel combinatorial libraries

Snively, C.M., Oskarsdottir, G. and Lauterbach, J. (2001) Parallel analysis of the reaction products from combinatorial catalyst libraries. Angew. Chem. Int. Ed., 40, 3028. 

Birkert O., Tunnemann R., Jung G., Gauglitz G., Label-Free Parallel Screening of Combinatorial Triazine Libraries Using Reflectometric Interference Spectroscopy, Anal Chem 2002 74 834. 

The recent development of parallel and combinatorial chemical library synthesis has created a renewed interest in polymeric solid-phase reagents. They offer the advantage of... 

The Pd-catalyzed carbonylation of o-vinylaryl bromides using Mo(CO)6 as CO source with microwave irradiation gave indanone 338 and 3-acylaminoindanone 340, which are key intermediates for the synthesis of inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and Plasmepsin I and II (Scheme 46). These polycyclic compounds were obtained in less than 30 min in high yields. The results clearly indicate the power and advantage of this protocol, especially for the combinatorial parallel synthesis of a library of compounds. 

OBRECHT Solid Supported Combinatorial Parallel Synthesis of Small Molecular-Weight Compound Libraries... 

In another example of combinatorial parallel chemistry, we have recently used the Ugi three-component reactions (Ugi 3-CR) to construct a library of 16,840 protease inhibitors (25). It has been demonstrated previously that the Ugi-3CR reaction provides a useful chemical scaffold for the design of serine protease inhibitors N-substituted 2-substituted-glycine /V-ary 1/alky 1 -amidcs have been identified that are potent factor Xa, factor Vila, or thrombin inhibitors. The three variable substituents of this scaffold, provided by the amine, aldehyde, and isonitrile starting materials, span a favorable pyramidal pharma-cophoric scaffold that can fill the S1, S2, and S3 pockets of the respective protease. This library was screened against five proteases (factor Xa, trypsin, uro-... 

In essence only two approaches exist to generate combinatorial peptide libraries biologic and synthetic library approaches. According to the different techniques used, the synthetic library approach can be divided additionally into five methods 1) the spatially addressable parallel library method (1, 4, 8),... 

Purity assessment of combinatorial hbraries is an important issne. It has led to the nse of alternative detectors next to MS, snch as UV-DAD and ELSD. Stractural characterization and pnrity assessment of compound libraries obtained by combinatorial parallel synthesis using LC-APCI-MS and MS-MS, UV-VIS DAD, and NMR has been reported by Dulery et al. [18]. 

The unpredictability of what components will constitute a successful sensing layer underlines the power of utilizing a 2D combinatorial parallel approach to the discovery of successful sensing systems in aqueous media. The library response toward metal cations can be used to search for either a unique response (individual hit ) or a whole fingerprint of responses. Here, the fingerprint is the collection of the individual responses of each sensing layer to one cation. Rapid inspection of the library fingerprint (Fig. 4.11) provides a unique response for each cation. 

Synthesis control has two tasks directly associated with it. These are to identify or verify the identity of a combinatorial component and to determine the purity of the synthetic product. When characterizing a parallel library it is a relatively easy task to obtain a molecular weight from a small amount (femto-mole) of compound and thereby obtain a crude identification of the product. This circumvents the need to perform more difficult NMR or IR spectral interpretation and sample introduction maybe performed by a simple flow-injection atmospheric pressure ionization (API)/MS system. Purity assessment is typically based on area percentage normalization of the total ion chromatogram, assuming equivalent ionization of impurities and parent compounds, or a secondary detector, such as UY... 

According to Blackwell [103] the application of microwave irradiation to expedite solid-phase reactions could be the tool that allows combinatorial chemistry to deliver on its promise - providing rapid access to large collections of diverse small molecules. Several different approaches to microwave-assisted solid-phase reactions and library synthesis are now available. These include the use of solid-supported reagents, multi-component coupling reactions, solvent-free parallel library synthesis, and spatially addressable library synthesis on planar solid support. 

Fig. 7.9. Representation of a combinatorial parallel synthesis of a 96-member library of dipeptides in a typical plastic microtiter plate of eight rows and 12 columns only the upper left three rows and three columns are shown. Step 1 shows three rows of wells containing three different amino acids that are already attached to a polymeric solid phase, as represented by the solid circles. In step 2, all eight rows are treated with the particular protected amino acids shown in each of the 12 columns, giving rise to 96 different polymer-bound dipeptides. In step 3, the dipeptides are cleaved from the solid support in preparation for testing them for biological activity.

As with other applications of combinatorial chemistry, libraries of catalyst candidates are mainly generated either by parallel synthesis (Scheme 3, middle) (6) or by the split-and-combine approach (Scheme 4) (7). Parallel (in many instances automated) synthesis has the advantage that the identity of the synthesis products (e.g., ligands) is known, and that existing methods of solution-phase synthesis (and analysis) can be applied with only little modification. 

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