Construction of libraries

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

Iba, Y., and Kurosawa, Y. (1997). Comparison of strategies for the construction of libraries of artificial antibodies. Immunol. Cell Biol. 75, 217-221. 

Both empirical and rational methods have been successful in developing novel fluorescent sensors. However, on the one hand, empirical design and synthesis may require considerable trial and error. On the other hand, the rational design approach described above is limited to analytes that can sufficiently change the oxidation or reduction potential. Further, even in the case of theoretically designed molecules, the fluorescence properties may be unexpectedly influenced by environmental factors. The construction of libraries of fluorescent molecules is one way to overcome some of these problems in the development of novel fluorescent sensors. 

Several different mutagenesis strategies have proven successful in the construction of libraries from which higher-affinity mutants have been selected (see Note 14). These include error-prone PCR (described in Subheading 3.2.1) and site-directed randomization. The latter technique is described below. 

An interesting three component reaction combining anilines, olefins and aldehydes forming tetrahydroquinolines was described by Grieco et and applied by Armstrong et al. for the construction of libraries based on this core structure is presented in Scheme 1.85.15. 

As foldamers are constructed from discrete monomer units, combinatorial methods are applicable to their synthesis. Much research has involved combinatorial construction of libraries of biomimetic foldamers [82]. Combinatorial methods have been used to study nonbiotic foldamers as well. For example, libraries of thiophenes have been studied [83], as have equilibrium mixtures of imine-linked pheny-lene ethynylenes [84]. 

To allow successful construction of libraries, a number of factors have to be considered to find an optimal compromise between the conflicting alms of a low frequency of background events and a high clone recovery in library construction. As described before (14,15), the ratio between inter- and intramolecular ligation events is determined by the ratio j/(i+j) between the effective local concentration j of one end of a... 

FIGURE 11.86 Octahydrobenzisoxazole scaffold for the construction of library 190 of over 2 million compounds. (From Tan, D.S. et al.. Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays, J. Am. Chem. Soc., 120, 8565, 1998 Tan, D.S., Synthesis and preliminary evaluation of a library of polycyclic small molecules for the use in chemical genetic assays, J. Am. Chem. Soc., 121, 9073, 1999.)... 

Natural epothilones have been structurally modified by various teams, making use of the broad stractural scope of natural product-based drag discovery in this field. Generally, this approach includes the de novo construction of libraries of natural product-like compoimds through diversity orientated synthesis (DOS) [17]. A concept for the design of natiual product-based libraries, introduced by H. Waldmann [18], has been developed over the last few years [19] (see also Sects. 1.2.1 and 1.2.2 in the introductory chapter). 

Sienczyk and co-workers have presented a rapid method for the construction of libraries of biologically active phosphonic pseudopeptides products (627-629) via Ugi and Passerini multicomponent condensations. As the starting material diaryl isocyanoalkylphosphonate (626) has been... 

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