Combinatorial library discrete

A convenient procedure for the solution phase preparation of a 2-aminothiazole combinatorial library has been reported. The Hantzch synthesis of 2-aminothiazoles has been adapted to allow the ready solution phase preparation of libraries of discrete 2-aminothiazoles <96BMC1409>. 

Combinatorial libraries have been prepared as discrete compounds or as mixtures with each approach having obvious advantages and disadvantages. Establishing the presence and purity of library members is straightforward when discrete compounds are synthesized. In addition, biological evaluation of discrete compounds directly corre-... 

Figure 14.1 The conceptual difference between the synthesis of a combinatorial library with exponential increase in number of compounds and the synthesis of parallel arrays of discrete compounds.

As first practiced by Geysen and Houghton, the preparation of combinatorial libraries produced discrete compounds of known identity through a technique known as "spatial separation," which simply means that individual compounds in the library are produced discretely and are not mixtures. Such spatially addressable compound sets are produced in such a way as to keep separate the reaction flasks or resin beads containing the individual components of the library and perform bioassays on the discrete compounds, one at a time. Thus, if the "history" of the reaction conditions performed in each flask or on each solid support, the identity of the compounds produced is known, without resort to structure elucidation techniques. Initially, this technique, after typically an extensive reaction development stage, allowed the preparation of between 10 and 1000 discrete combinatorial products. 

Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds... 

The directed sorting approach is a convenient technology to produce large combinatorial libraries of discrete compounds. As can be seen with the two examples presented, it is a very versatile and practical method to produce compounds in a variety of formats. 

Dynamic combinatorial chemistry (DCC) is founded on the study and the construction of mixtures of discrete constituents which are produced by reversible molecular or supramolecular associations [1, 2], The composition of a dynamic combinatorial library (DCL) is thermodynamically driven and, as such, is able to adapt itself to any parameter that - permanently or transiently - modifies its constitution/energy potential surface [3,4], Thus, in the presence of various internal or external parameters, the involved equilibria can be displaced toward the amplification of given products through an adaptation process that will occur through an in situ screening of these species. A schematic representation using Emil Fisher lock-and-key metaphora can be used to illustrate these concepts (Fig. 1). 

Some companies (75, 76) have developed their own automated instruments for combinatorial library synthesis in solution to produce large, purified arrays of discretes (up to several tens of thousands of individuals) the available information is obviously scarce, but an example of such a proprietary integrated synthesizer will be presented in section 8.2.6. 

The switch from single compounds to a combinatorial library in solution increases the complexity of the potential issues to be addressed, as we have seen in the previous chapters. The same is true for the purification of these libraries, which cannot rely on simple filtration and washing of the resin beads, as in the SP chemistries. The separation techniques of classical chemistry are used. However, general, automated methods applicable to all members of a library have to be found. Usually, these methods are also applicable to the final purification of cleaved SP libraries, either as discretes or as pools. 

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

In the synthesis of combinatorial libraries, there is a raft of tactical issues that need to be tackled. Will the library be made of mixtures or discrete compounds Prepared by solid-phase or solution-phase Screened in solution or attached to beads What level of purification and characterization is needed Will hits be identified by deconvolution, encoding techniques, or other means These are aU crucial operational aspects of combinatorial chemistry but it is equally important not to concentrate on them to the extent of missing the big picture. At the end of the day, neither a biological assay nor a medicinal chemist care how a compound was made. It is vital, though, that the tactical decisions do not prevent one from making the right compounds. Combinatorial synthesis is a means to an end, not an end in itself. 

Traditional combinatorial libraries are synthesized primarily by parallel or split-pool techniques as static pools of discrete... 

Although combinatorial libraries were originally synthesized as mixtures, today most libraries are prepared in parallel as discrete compounds and then screened individually in microtiter plates of 96-well, 384-well, or 1536-well formats. To facilitate subsequent structure-activity analyses and to assure the validity of the screening results, many laboratories verify the structure and purity of each compound before high-throughput screening. Semi-preparative HPLC has become the most... 

Theoretical and experimental results by Blom (45) have focused on the precision requirements for the mass spectrometric analysis of combinatorial library mixtures. In his work, Blom has used discrete mass filters in combination with mass-MS/MS, M + 1/M, and M + 2/M isotope ratio filters to determine library components specifically from peptide libraries. As pointed out below, while nonpeptide libraries have mass distributions that are completely random, peptide library building blocks are limited in their diversity,... 

The corresponding combinatorial libraries (CLs) eonsist in large, static populations of different, discrete molecules prepared by the methodologies of molecular chemistry and derived from a set of units connected in various sequences by the repetitive application of specific chemical reactions, with the aim of producing as high a structural diversity as possible [1-6]. This procedure can, of course, be extended to other areas, such as the combinatorial preparation of multicomponent materials and the rapid screening for their physical properties or the discovery of novel catalyst for specific reactions. 

From this basic list of 12 nano-element categories, a nano-element road map leading to three combinatorial libraries of nanocompounds and nano-assemblies can be envisioned, namely, [hard-hard], [hard-soft], and [soft-soft] types as illustrated in Fig. 18. These nanocompounds and nano-assembUes can be characterized analytically by the proportion of each of these 12 basic nano-elements they contain, based on their discrete bonding/assembly capacities, valencies, stoichiometries, and mass-combining ratios. Many examples of these stoichiometric nanocompounds and assemblies are already documented in the literature and are described in more detail elsewhere [137, 138]. 

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