Xanthene library

Sadowski etal. [49] have described the use of 3D autocorrelation vectors that are based on the electrostatic potential measured on the molecular surface of a molecule. The electrostatic potential was measured over 12 different distances giving 12 autocorrelation coefficients per molecule. The vectors were calculated for the molecules in two different combinatorial libraries a xanthene library and a cubane library. The compounds were then used to train a Kohonen network. The network was successfully able to separate the libraries. 

Direct ES-MS characterization of a combinatorial library has been performed on the example of modified xanthene derivatives [30]. To circumvent the analysis of 104 to 10s possible compounds, small representative sublibraries rather than the whole library were synthesized and investigated [31].The results obtained were then extrapolated to the synthesis of the target library. A xanthene library was also used for ES-FT-ICR-MS investigation [32], A more recent contribution deals with the calculation of elemental compositions from FTICR mass spectra. FIowever,the mass accuracy required increases exponentially with the mass of the analyte [33], Therefore, elemental compositions are calculated from the exact measurement of fragment ions performing MS"-experiments [34],... 

Other popular scaffolds have been derivatives of biphenyls which are now readily prepared using solid phase methods [265,464-469]. A solution phase approach has been to react a polyfunctional ised core containing reactive groupings - acid chlorides or isocyanates are easily prepared examples -with a mixture of reagents. One of the earliest synthetic examples showed the use of cubane tetracarboxylic acid chloride [151]. Two recent methods have used functionalised xanthene (library 71) [470] or diphenylmethane cores (library 72) [471] to identify DNA and urokinase receptor antagonists respectively. 

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. 

This approach was reported by Carell et al. [30] and, whilst it has often been cited with the name subtractive deconvolution, it could be also named tailored deconvolution. One of the libraries deconvoluted by this method, and targeted to trypsin inhibition, was prepared in solution adding equimolar amounts of 19 amino acids (Gin excluded) to a tetrafunctional xanthene scaffold, to produce a solution library composed of 65,341 individuals as a single pool (Figure 8.7). The extensive chemical and analytical assessment which assured the quality of the library included synthesis of six smaller model libraries (30-60 compounds), using simplified xanthene scaffolds, and their thorough MS characterization. Further details are not presented here, being out of the purpose of this review, but the conclusions about the library quality can be safely accepted. 

FIGURE 8.7 Synthesis of a xanthene-based pool library. 

More unique are the xanthene and cubane cores (Figure 5) chosen by Rebek for the solution-phase synthesis of highly pooled combinatorial libraries in a single step. By iterative deconvolution, a thrombin inhibitor was identified from this complex collection. Similarly, workers at Isis reported the functionalization of a novel polyazacyclophane core, which led to the discovery of antibacterial leads. Clearly, in both these cases, the hits are structurally unrelated to common drug-discovery scaffolds. 

Dunayevskiy et al. showed the ability of HPCE-MS to determine the purity and composition of a library theoretically composed of 171 disubsti-tuted xanthene derivatives, with the possibility of analyzing libraries of up to 1000 components (92). Previously, the ability of MS alone to analyze a library of up to 55 components was shown (93), but it was suggested that for more... 

Capillary electrophoresis (CE) is a powerful separation technique. It is especially useful for separation of ionic compounds and chiral mixtures. Mass spectrometry has been coupled with CE to provide a powerful platform for separation and detection of complex mixtures such as combinatorial libraries. However, the full potential of CE in the application of routine analysis of samples has yet to be realized. This is in part due to perceived difficulty in the use of the CE technique compared to the more mature techniques of HPLC and even SFC. Dunayevskiy et al. [136] analyzed a library of 171 theoretically disubstituted xanthene derivatives with a CE/ESI-MS system. The method allowed the purity and makeup of the library to be determined 160 of the expected compounds were found to be present, and 12 side products were also detected in the mixture. Due to the ability of CE to separate analytes on the basis of charge, most of the xanthene derivatives could be resolved by simple CE-MS procedures even though 124 of the 171 theoretical compounds were isobaric with at least one other molecule in the mixture. Any remaining unresolved peaks were resolved by MS/MS experiments. The method shows promise for the analysis of small combinatorial libraries with fewer than 1000 components. Boutin et al. [137] used CE-MS along with NMR and MS/MS to characterize combinatorial peptide libraries that contain 3 variable positions. The CE-MS method was used to provide a rapid and routine method for initial assessment of the construction of the library. Simms et al. [138] developed a micellar electrokinetic chromatography method for the analysis of combinatorial libraries with an open-tube capillary and UV detection. The quick analysis time of the method made it suitable for the analysis of combinatorial library samples. CE-MS was also used in the analysis... 

Scheme 3.1. Preparation of a combinatorial library of xanthene teracarboxamides as a mixture.

In order to use this template approach in view of synthesising combinatorial libraries of mimetics of exposed protein loops, Waldmeier and Obrecht synthesised the unsymmetrically substituted xanthene derived templates 11 and 12 Figure 23.6)P... 

Thus, if we allow pairs of enantiomorphic amino acids and the self-enantiomorphic amino acid glycine, i.e. total sets of 3, 5,..., up to 39 amino acids, we find that the combinatorial libraries of all the possible amidation products consist of 25,169,..., up to 579,121 tetra-amides of this particular xanthene-tetracarboxylic acid. The libraries contain 20,156,..., and 578,360 enantiomorph amidation products, and 5, D..., 761 self-enantiomorphic ones, respectively. 

Example (Libraries of amidations of a xanthene) Recall the skeleton used in Chapter 3, xanthenetetracarboxylic acid chloride ... 

To prove that SOMs can also be used to assess the similarity of chemical libraries, a second network was trained using an additional virtual library based on the adamantane core functionalized at the four bridgehead positions Figure 8(c). As shown in Figure 9(b), the SOM again discriminated very effectively between the xanthene and cubane/adamantane derivatives, but was unable to distinguish the cubane from the adamantane library, which is consistent with the conformational constraints imposed by their rigid cores. 

Figure 9 Self-organizing maps of (a) the xanthene (light gray) and cubane (black) libraries and (b) the xanthene (light gray), cubane (black), and adamantane (dark gfay) libraries...

Figure 11 Non-linear map of the xanthene (blue), cubane (green), and admantane (red) libraries used by Gasteiger el al.

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