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High-Throughput Quality Control Assay for the Solid-Phase Syn-thesis of DNA-Encoded Libraries of Macrocycles
preprintsubmitted on 28.12.2020, 15:08 and posted on 29.12.2020, 08:46 by Animesh Roy, Thomas Kodadek
There is considerable interest in the development of libraries of scaffold-diverse macrocycles as a source of ligands for difficult targets, such as protein-protein interaction surfaces. A classic problem in the synthesis of high-quality macrocyclic libraries is that some linear precursors will cyclize efficiently while some will not, depending on their conformational preferences. We report here a powerful quality control method that can be employed to readily distinguish between scaffolds that do and do not cyclize efficiently during solid-phase synthesis of thioether macrocycles without the need for tedious liquid chromatography/mass spectrometry analysis. We demonstrate that this assay can be employed to identify largely linear “impurities” in a DNA-encoded library of macrocycles. We also use the method to establish a useful quality control protocol for re-synthesis of putative macrocyclic screening hits.