Solid-phase synthesis 634 INDEX

As in solid-phase synthesis programs, one of the most challenging problems with solution-phase synthesis is to separate products obtained in the reaction mixtures and identify the compound or compounds with biological potency or some other desirable property. An especially effective technique that has been developed to deal with this problem is called indexed libraries, also known as orthogonal libraries. In this process, each product compound is prepared twice. Analysis then permits identification of the positive part of the compound and the negative part of the compound with the greatest potency. Once these have been determined, it is possible to identify the specific compound most active in the mixture. 

Bunin BA. The combinatorial index. In Combinatorial Solid-Phase Synthesis. 1998. Academic Press, pp. 77-82. 

Zefirov NS, Sereda GA, Volkov PV, Tkatchenko SE, Zyk NV. Solid-phase synthesis of 1,2-benzophenazine and some fused imidazole derivatives. Chem Heterocycl Comp 1996 32 577-9. (Khim Geterotsikl Soedin 1996 672-4) ECHET98. http //www.ch.ic. ac.uk/ectoc/echet98/pub/097/index.htm. 

Positional scanning, or 1-D indexing, was reported as a deconvolutive technique by Houghten and coworkers [35] and subsequently applied extensively to solid-phase peptide library synthesis. An example of solid-phase small organic molecule 2-D indexed library synthesis and deconvolution was reported by Berk et al. [36]. Description of this strategy, called spatially arrayed mixture (SpAM), and a comparison with classical positional scanning, are shown in Figure 8.9. 

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]. 

SPPS - Solid phase parallel synthesis SPMS - Solid phase split-mix synthesis Ind - Indexed ID - Iterative deconvolution... 

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

Contents Introduction. - Structure Determination Amino Acid Analysis. Sequence Determination. Secondary and Tertiary Stmcture. - Peptide Synthesis Formation of the Peptide Bond. Protection of Functional Groups. Undesired Reactions during Synthesis. Racemization. Design of Schemes for Peptide Synthesis. Solid Phase Peptide Synthesis. - Methods of Facilitation. Analysis and Characterization of Synthetic Peptides. -Subject Index. 

This combination of solid-phase peptide synthesis followed by TE-mediated macrocyclization mimics the function of NRPSs, in which a peptide chain is first elongated and then cleaved and often cyclized. The applicability of this approach for the discovery of NCEs is apparent established synthetic combinatorial methods could be employed in concert with the enzymatic machinery of the NRPS. In the case of the tyroddine A Ubrary, two analogs were discovered that displayed both improved antibiotic activity and a better in vitro therapeutic index (human erythrocytes vs. Gram positive/negative bacteria) relative to the parent tyroddine A. 

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