High‐Throughput Quality Control Assay for the Solid‐Phase Synthesis of DNA‐Encoded Libraries of Macrocycles. (14th April 2021)

• Record Type: Journal Article
• Authors: Roy, Animesh; Koesema, Eric; Kodadek, Thomas
• Is Part Of: Angewandte Chemie. Volume 133:Number 21(2021)
• Page Start: 12090
• Page End: 12097
• Publication Date: 2021-04-14
• Subjects: DNA-encoded libraries -- macrocycles -- peptidomimetics; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202100230
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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 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. Abstract : The creation of high‐quality libraries of macrocycles from conformationally restricted precursors is a challenge due to the variable cyclization rates of different linear molecules. Here we report a powerful assay for on‐resin analysis of the cyclization efficiency of thousands of non‐peptidic thioether macrocycles in the context of a DNA‐encoded library.