Deluge Biotechnologies, 6671 W. Indiantown Rd., Suite 50-325, Jupiter, FL, 33458, USA.
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
Angew Chem Int Ed Engl. 2021 May 17;60(21):11983-11990. doi: 10.1002/anie.202100230. Epub 2021 Apr 13.
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.
人们对支架多样化的大环文库的开发很感兴趣，因为它可以作为配体来源，用于靶向难以结合的目标，如蛋白质-蛋白质相互作用表面。在高质量大环文库的合成中，一个经典问题是，一些线性前体根据其构象偏好，会有效地环化，而有些则不会。我们在这里报告了一种强大的质量控制方法，可以在不进行繁琐的液相色谱/质谱分析的情况下，在固相合成硫醚大环时，很容易区分有效和无效环化的支架。我们证明，该测定法可用于鉴定 DNA 编码大环文库中的线性杂质。我们还使用该方法为重新合成假定的大环筛选命中物建立了有用的质量控制方案。
