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High‐Throughput Quality Control Assay for the Solid‐Phase Synthesis of DNA‐Encoded Libraries of Macrocycles **
Author(s) -
Roy Animesh,
Koesema Eric,
Kodadek Thomas
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202100230
Subject(s) - thioether , combinatorial chemistry , solid phase synthesis , dna , chemistry , throughput , scaffold , quality (philosophy) , mass spectrometry , computational biology , computer science , nanotechnology , chromatography , materials science , biochemistry , stereochemistry , biology , physics , database , peptide , telecommunications , wireless , quantum mechanics
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.