Combinatorial libraries solid-phase

Amino Acids, Chemical Properties of Click Peptides, Design and Application of Peptide Combinatorial Libraries Solid-Phase Synthesis of Biomolecules... 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

Two general methods are used to build a library of compounds by the general techniques of combinatorial chemistry solid-phase synthesis (SPS) and solution-phase synthesis. 

Taylor, C. M. The sulfoxide glycosylation method and its application to solid-phase oligosaccharide synthesis and the generation of combinatorial libraries. Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries 2001,41 -65. 

DB Kassel. A fully automated mass spectrometry based system for the rapid analysis and purification of combinatorial libraries. Solid and Solution Phase Combinatorial Synthesis, New Orleans, 1997. 

Combinatorial chemistry has become one of the main tools for the rapid construction of molecular libraries for use in drug discovery and in biology. Important factors for the design of these libraries are structural diversity and complexity, which have to be balanced with size and purity of the individual compounds. For the construction of these libraries, solid phase chemistry has become a basic technique... 

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... 

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 chemistry (Section 27.18) A method for carrying out a large number of reactions on a small scale in the solid phase so as to generate a library of related compounds for further study, such as biological testing. 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

The Biginelli reaction has also been extended to solid phase and combinatorial synthesis. In a recent combinatorial approach Kappe and coworkers used 4-chloroacetoacetate as a building block to create a library of diverse DHPMs under... 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

Beausoleil, E., Truong, K.T., Kirshenbaum, K., and Zuckermann, R.N. Influence of monomer structural elements in hydrophilic peptoids. In Innovations and Perspectives in Solid Phase Synthesis and Combinatorial Libraries Peptides, Proteins, and Nucleic Acids, R. Epton (Ed.), 2001, Mayflower Scientific Press Kingswin-ford, UK, pp. 239-242. 

Certain types of molecules, especially polypeptides and polynucleotides, lend themselves to synthesis on solid supports. In such syntheses, the starting material is attached to a small particle (bead) or a surface and the molecule remains attached during the course of the synthetic sequence. Solid phase synthesis also plays a key role in creation of combinatorial libraries, that is, collections of many molecules synthesized by a sequence of reactions in which the subunits are systematically varied to create a range of structures (molecular diversity). 

P. A. Keifer 1998, (New methods for obtaining high resolution NMR spectra of solid-phase-synthesis resins, natural products, and solution-state combinatorial chemistry libraries), Drugs Future 23, 301-307. 

Recently, a solid-phase synthesis was used iteratively for the synthesis of organic substances like oligocarbamates [13] and oligoureas [14] by repeated coupling to amino-functionalized supports. In this way substance libraries [15] have been developed showing that iterative methods can also be employed in combinatorial chemistry [16]. 

Fig. 10 Synthetic scheme for the construction of rosamine library using solid-phase combinatorial approach. Average emission values of fluorescent compounds derived from each rosamine moiety are presented below the structure of rosamine moieties. (All the emission wavelengths were obtained in PBS buffer)...

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