Solid phase libraries

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. 

For solution-phase libraries that are composed of mixtures of compounds, the difficulty of analysis escalates with increasing numbers of compounds. Typically, large mixtures of compounds are not analyzed before screening, whereas small ones may be analyzed for reaction completeness using mass spectrometry, HPLC, NMR, or combinations thereof. The identification and analysis of active compounds from these mixtures is painstakingly tedious, and often complete characterization is possible only after deconvolution procedures and resynthesis of the active compound. For solid-phase libraries, the methods currendy developed are discussed below. 

The technique of preparing target compounds in a solid-phase library whereby resin-bound intermediates in the preparation of a solid-phase library are combined and then redivided for attachment of subsequent monomers. This technique produces mixtures of compounds but allows for the rapid production of very large compound libraries... 

Defining the structural identity of a resin-bound compound in solid-phase library by marking the individual resin beads with a tag that is unique to the attached target compound... 

A solid phase library synthesis method based on the Fischer indole synthesis was developed (Scheme A resin-capture-release method... 

Alternatively, starting this time from aryl isocyanides, the secondary amide can be activated by conversion into an imide by the treatment with B0C2O [29, 38,41]. This strategy was employed in the synthesis of compounds 15,17 and 19 [29], and is particularly appropriate for solid-phase library synthesis. 

The synthesis of 1,2,4-triazole-fimctionalized solid support 72 and its use in the solid-phase synthesis of various tiisubstituted 1,2,4-triazoles 73 was reported <990L1189>. A solid-phase library synthesis of triazolopyridazines 76 was achieved by [4+2] cycloaddition of diene amides 74 with 4-substituted urazines 75 <99TL619>. 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

H. Gotfredsen, M. Grotli, M. Willert, M. Meldal and J. O. Duus, Single-bead structure elucidation. Requirements for analysis of combinatorial solid-phase libraries by Nanoprobe MAS-NMR spectroscopy, J. Chem. Soc. Perkin, 2000, 1, 1167-1171. 

Split/pool solid-phase libraries and solution-phase pools... 

Using the well-known technique of positional scanning [122, 123], solid-phase libraries were inspired by a standard structure derived from preliminary experiments (AA1=L-Phe, AA2 = L-Val, ArCHO = 2-hydroxy- 1-naphthylal-dehyde) and produced 45 different ligands in three sublibraries. AA1, AA2, or ArCHO were randomized, while keeping the other two building blocks as in... 

Structure determination of components of pool libraries can be divided into two main classes. The first, which is the subject of this review, is called direct deconvolution. It does not require any additional construct in order to determine the structure of a library component and is normally applied to solid-phase libraries, although examples of solution libraries will also be presented. The second, which will be discussed in the following review, is called encoding because a unique code, either chemical or non-chemical, is linked to each library component and its reading allows the structure determination of the compound. It is applicable only to solid-phase libraries, and it requires additional constructs to be added to the library structure. 

Positional scanning was repeatedly used by Houghten and coworkers [38] in solid-phase peptide synthesis, but few examples of its application to small molecule libraries have been reported. Smith et al. [39] deconvoluted a solid-phase library of 1600 esters/amides, Andrus et al. [40] deconvoluted a solid-phase library of non-natural polyenes, Leone-Bay et al. [41] deconvoluted the activity of an indexed library in an in vivo assay, while Pirrung et al. reported both a solution phase 54-member carbamate library [42] and a solution-phase 72-member tetrahydroacridine library [43]. 

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

Arya, P., Wei, C.-Q., Barnes, M. L., Daroszewska, M. (2004) A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsrmobu approach. Journal of Combinatorial Chemistry, 6, 65—72. 

EXAMPLE FOR MONITORING THE REHEARSAL PHASE OF THE SYNTHESIS OF A SOLID-PHASE LIBRARY... 

Ugi, i., Domiing, A., Gruber, B., Heck, S., Heiiingbrunner, M. From iiquid-phase muiticomponent reactions to solid phase libraries. 

It is generally accepted that the translation of solution-phase reactions to solid-phase procedures for the production of compound libraries is usually time-consuming and not always successful. The most robust solid-phase synthesis instrumentation has operational temperature and solvent compatibility limitations that impinge on the direct translation of solution-phase chemistries to the solid phase. These instrument restrictions necessitate a considerable investment in experimentation to rcdclinc the solution-phase reaction protocol for the solid phase. In spite of this apparent obstacle, a substantial number of reactions for solid-phase library production has been pubhshed. Many of these reachons cannot be exploited because the overall product yields are too low (which could lead to ambiguity in the interpretahon of the eventual assay results). Also, some reachons have a restricted range of potential monomers that lead to a hmited diversity of the compounds in the resulting library. 

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