Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.
Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, 44221, Dortmund, Germany.
Angew Chem Int Ed Engl. 2021 Feb 23;60(9):4648-4656. doi: 10.1002/anie.202013731. Epub 2021 Jan 12.
Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo-NPs, NP-derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155-member pyrroquinoline pseudo-NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological "cell painting" assay followed by principal component analysis revealed that the pseudo-NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
天然产物 (NP) 结构是发现新的具有生物学相关性的化学物质的丰富来源。在受天然产物启发的伪 NP 中，NP 衍生片段以前所未有的方式重新组合。本文设计并合成了 155 个成员的吡咯喹啉伪 NP 化合物库，其中包含四氢喹啉和吡咯烷 NP 类特征片段，与八种不同的连接方式和区域异构体排列方式相结合。通过形态“细胞染色”测定中的表型进行化合物库的化学信息学分析和生物评价，然后进行主成分分析，结果表明伪 NP 类具有化学多样性，并且活性模式明显不同，这取决于片段的连接方式和区域异构体排列方式。
