Libraries chemically encoded

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 6.10 Chemical encoding of resin beads. Branched linkers, with one site for attaching the library compound and another for attaching the tag, are often used for encoding...

Chemical encoding aims to prepare a one bead one compound [5, 7] solid-phase library. At first sight a comparison reveals apparent drawbacks with... 

As previously observed [41] this synthesis produced more than one isomer during the cycloaddition (three chiral centers are formed), so that the final library contained more than 500 individuals and the stereochemical outcome varied, depending on the nature of Rl5 R2 and R3. Any chemical encoding could not account for stereochemical reaction outcomes, so that each stereoisomer from positive beads was prepared pure and its activity was determined after library synthesis, biological testing, and decoding. 

Garigipati and Adams [61] reported a chemical encoding procedure, based on novel photochemically cleavable aryl sulfonamides as inert tags with a robust and reliable chemistry. An example of a 1000-member encoded library was provided without experimental details, so additional applications of these chemical tags need to be disclosed in order to have a better understanding of their strengths and limitations. 

Any chemically encoded library requires a double orthogonal chemical strategy, or the construction of elaborate tags/linkers on the solid support prior to the synthesis. Even when these are easily prepared and inert, the synthetic scheme becomes more complicated than direct deconvolution methods, where only the library synthesis is required. Sometimes the tag chemistry and the... 

The discovery of chemical encoding technologies and radio-frequency (Rf) encoded synthesis have had a major impact on synthesis of lead discovery libraries. Both technolo-... 

Another decoration pool library L23 was reported by Nestler (49), who presented the appendage of a peptidic chain to the two hydroxylic functions of a steroid scaffold (Fig. 4.15). The library was made up of 10 x 10 x 10 x 10 = 10,000 individuals using a chemical encoding method (39) and L-a-amino acids as monomer sets (R1-R4). The assay of the library as a source of artificial two-armed receptors for enkephalin-related peptides produced positives with micromolar affinity. Much larger libraries could be obtained by simply increasing the monomer sets and the length of the two arms this could lead to a primary library of peptide-binding artificial receptors similar scaffolds have been repeatedly exploited for combinatorial purposes (50-52). 

The primary library shown in Fig. 5.2, which was reported by Baldwin (1), was clearly designed as a source of biologically active molecules on several targets (why), thus compensating the efforts required for the chemical assessment and for a satisfactory characterization (when). The SP library was prepared in pools using chemical encoding (4, 5) to produce a population of around 62,000 individuals (how). The synthetic scheme was composed of both simple and more complex SP steps, and several monomer sets (A-F, Fig. 5.2) were used (what). These monomers were either commercially available or easily prepared from commercial precursors, while the library benzopyranic core was formed during the synthesis (how much). 

Figure 7.23 Hypothetical SP synthesis of a 1000-member pool library using chemical encoding.

A family of chemical tags should ideally possess a number of features. It should be stable to all, or to the large majority, of the reaction conditions that may be used in an SP hbrary synthesis its synthesis should be easy and almost quantitative using commercially available precursors its presence should not interfere with the library synthesis scheme it should be inert in library screening when on-bead methods are used its structure should be determined with a fast and reliable method. We will now present the various chemical encoding strategies reported in the hterature and will comment on their fulfillment of the above criteria. 

Chemically encoded, bead-based SP pool libraries Several chemical tagging methods exemplified Several tagged SP libraries exemplified... 

OBOC combinatorial bead-libraries can be considered as chemical microarrays that are spatially separable but non-addressable. The identity of the chemical compound on the positive beads can be determined directly with an automatic sequencer if it is an N-terminally unprotected peptide, by mass spectroscopy, or through chemical encoding. i A synthetic scheme for the OBOC library is shown in Figure 2. Using the highly efficient split-mix synthesis method,literally hundreds of thousands to millions of compounds can be prepared within a week. The recent... 

The main limitations of chemically encoded libraries are the necessity to perform an extra chemical reaction at each step to introduce the coding tag, the... 

Radiofrequency tags encapsulated in grafted functionalized polymers have recently been reported (53), as have laser optical-encoded ceramics with grafted polystyrene supports (54). These devices have the properties of really big beads that contain the identifying tag and thus combine the features of chemically encoded libraries with the advantages of mechanically encoded libraries. 

Chemical encoding strategies rely on the assumption that the chemical analysis of a given member of the library is more difficult than the analysis of a chemical tag. In most cases this assumption is valid and justifies the described technique. Some libraries have been prepared and characterized by individual mass spectrometric analysis of each member of the library. However, to obtain unambiguous results, the following criteria must be fulfilled ... 

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