Library discrete compound

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-... 

The solid-phase technique of split and mix synthesis relies on the efficiency of mixture-based synthesis to provide very large libraries (millions) of discrete compounds (Figure 4).[161 In this approach, each resin bead is treated with a single building block for each synthesis step. Thus any single resin bead possesses identical copies of one library member, but the identity of the library member on any bead is lost due to the mix step of the process. Elegant strategies have been developed to chemically encode the syn-... 

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. 

Alternatively, the so-called mix-and-split method [17-22] can be used to prepare mixtures of support particles (beads, paper disks, etc.) or of small portions of support (e.g., tea bags ) with a well-defined quantity of one discrete compound linked to each portion of support. These compound libraries can be screened either directly on the support, or in solution after partial or total cleavage of the product from the support. 

Registration This is an abstraction that represents a compound registration transaction. A registration can be for a single compound, a group of discrete compounds, or a compound library. 

Tire source code of the LibraryChemistryProcessCommand, which processes chemistry logic on a chemical library, is as follows. (You can have another Command object to process discrete compounds. The idea is the same.)... 

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

The directed sorting method has also been used to produce a large amount of compound (up to 100 mg).26 In the following example, the method was used to generate 100 mg of 3-aminobenzothiazepine derivatives. Each derivative was then acylated with 20 different carboxylic acids using the tetrafluorophenol resin (TFP-resin).27 Overall this allowed a large library of 16,000 discrete compounds to be produced. 

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. 

Purification A variety of creative and innovative open-access LC/MS formats were developed to address throughput needs within the industrial laboratory. As the preparation of large libraries for lead discovery became routine, the burden placed on analytical techniques focused mainly on throughput and quality (Kyranos and Hogan, 1998 Van Hijfte et al., 1999). Biological assay requirements, however, normally required pure compounds. Thus, the focus shifted toward the use of automated high-throughput purification methods applied to libraries of discrete compounds (Weller, 1998-99). 

This issue highlights the characterization difference between parallel synthesis and combinatorial synthesis. Parallel synthesis is automated traditional organic chemistry. Each compound is made in a separate reactor, purified and characterized. There is no excuse for not fully characterizing compounds made by parallel synthesis. Jonathan Ellman s laboratory at UC Berkeley has been a pioneering academic center for solid-phase chemistry development. His philosophy is to synthesize libraries of discrete compounds in a spatially separate fashion, rather than libraries of compound mixtures, to allow for rigorous analytical characterization [48,49],... 

Libraries prepared by application of real combinatorial synthetic methods are usually submitted to screening experiments, either as soluble mixtures or as unknown discrete compounds cleaved from, or tethered to individual beads of the solid support. The task in deconvolution is to identify the substance that has a desired property. The deconvolution methods can be classified into two groups deconvolution of mixtures, cleaved from support and deconvolution of tethered libraries. 

As already mentioned, components of libraries produced by the original split-mix method are discrete compounds. If the libraries are cleaved from the solid support, however, mixtures are formed. The products of the liquid phase synthesis are always mixtures. At the beginnings, finding an active component in a mixture of thousands, or millions of structurally related compounds seemed to be a task like finding a needle in a haystack. Later on, however, reliable methods have been developed to solve this problem. All these methods are based on preparation and screening of properly designed partial libraries. 

The selected examples by Keating and Armstrong [59, 60] reported the synthesis of a small discrete solution library (eight compounds) of Ugi 4CC products and their further elaboration. The concerted mechanism of the Ugi 4CC is shown in Figure 7.5. The scarcity of commercial isocyanides encouraged the use of a convertible isocyanide [59, 60], which allowed its postcondensation transformations in other functional groups, which are shown in Figure 7.6. 

These libraries contain a relatively small number of individuals (typically tens to hundreds) and are almost always prepared as discrete libraries using parallel synthesis and automated or semiautomated devices. Focused libraries are predominantly prepared in solution because of the easier shift from classical organic synthesis to solution-phase combinatorial chemistry, while automated purification procedures for relatively small arrays of discrete compounds in solution are common nowadays. The... 

The main purpose of parallel high-throughput organic synthesis (HTOS) is, as already mentioned in Chapter 4, to prepare focused libraries of discrete compounds that can be used to assess a fast, preliminary stmcture-activity relationship for a specific target. The components of these libraries may vary in number from tens to thousands of compounds therefore different instrumentation and expertise are required depending on the library size. 

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. 

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... 

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