Compound libraries parallel analysis

Almost all of the analytical characterization tools (e.g., HPLC, NMR, FTIR, and LC/MS) are serial-based techniques, and parallel synthesis is inherently parallel. Consequently, this led rapidly to a new bottleneck in the discovery process (i.e., the analysis and purification of compound libraries). Parallel synthesis suffers from some of the same shortcomings of split and mix synthesis (e.g., the expected compound may not be pure, or even synthesized in suffi-... 

Performing parallel analysis of compound libraries offers many potential advantages over serial-based LC/MS analytical methods, the most obvious of which is dramatically increased compound analysis throughput. Using singlechannel HPLC-based purification systems, routine sample throughput of up to 192 reaction mixtures per 24-hour day was reported [64]. With parallel HPLC systems, it has been reported that the theoretical throughput increases to 384 samples per day for a two-channel system and to 768 samples per day for a four-channel system. 

B.D. Dulery, J. Veme-Mismer, E. Wolf, C. Kugel, L. Van Hijfte, Analysis of compound libraries obtained by high-throughput parallel synthesis strategy of quality control byLC, MS and NMR techniques, J. Chromatogr. B, 725 (1999) 39. 

T Wang, J Cohen, DB Kassel, L Zeng. A multiple electrospray interface for parallel mass spectrometric analysis of compound libraries. Comb Chem High Throughput Screen 2(6) 327—334, 1999. 

Cremin, P.A. Zeng, L. High-Throughput Analysis of Natural Product Compound Libraries by Parallel LC-MS Evaporative Light Scattering Detection, Anal. Chem. 74, 5492-5500 (2002). 

Fast LC-MS methods have been used to assess library quantity and purity, as well as to triage purification of compounds. Zeng et al. [51] developed one of the first fully automated analytical/preparative LC-MS systems for the characterization and purification of compound libraries derived by parallel synthesis. The system incorporated fast, reverse-phase LC/ESI-MS analysis (5-10 minutes). Post-data-acquisition purity assessment of compound ti-braries was performed automatically with software control. Compounds that were below a threshold level of purity were automatically purified with HPLC. The real-time purity assessment eliminated the need for postpurification analysis or pooling of fractions collected. 

The isolation of natural products from organisms generally yields compound libraries covering large areas in diversity space. In some cases, sets of structurally related natural compounds are isolated (see Section 5.4) that are suitable for an initial analysis of SAR. Mostly, however, further structural variations and focused libraries are required for in-depth determination of SAR and lead optimization. The new paradigm for creating such small-molecule libraries by combinatorial and parallel synthesis has been successfully apphed to natural product synthesis and enabled chemists to build arrays of derivatives based on a common natural product template. ... 

While parallel synthesis of arrays of glycopeptides is readily achieved by implementation of the building-block approach (Scheme 14.1, Strategy 2),101 glycopeptide library synthesis in a combinatorial manner via the split-mix method has yet to prove routine. The difficulty lies in the structural analysis of the vast number of compounds generated in picomolar quantities on a single bead. Whereas peptides on... 

The significant advantage of the parallel LC/MS system is its throughput. Because eight LC/UV/MS analyses can be conducted simultaneously, the total analysis time is decreased by a factor of eight. To analyze every compound in a library of 2500 compounds at 3.5 min cycle time requires 146 h using a single channel LC/UV/MS system. However, it requires only... 

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