Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Street 11, 44227, Dortmund, Germany.
Ruhr University Bochum, Faculty of Chemistry and Biochemistry, Organic Chemistry II, University-Street 150, 44801, Bochum, Germany.
Angew Chem Int Ed Engl. 2023 May 15;62(21):e202301955. doi: 10.1002/anie.202301955. Epub 2023 Apr 18.
Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective Rh -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.
氧化吲哚和异氧化吲哚是天然产物衍生的支架，为设计和合成新型生物相关化合物类提供了灵感。值得注意的是，氧化吲哚与异氧化吲哚的螺环连接尚未被自然界探索，但有望提供具有新型生物活性的结构相关化合物。因此，高效合成它们的方法和明确发现它们的细胞靶标是非常需要的。我们描述了一种选择性 Rh 催化的螺环氧化吲哚-异氧化吲哚和螺环氧化吲哚-氧化吲哚的支架发散合成方法，该方法使用不同保护的重氮氧化吲哚和 N-特戊酰氧基芳酰胺作为起始原料，其中包括关键步骤的功能基团控制的Lossen 重排。在细胞画测定中的相应化合物库的无偏形态分析有效地鉴定了有丝分裂驱动蛋白 Eg5 为螺环氧化吲哚的细胞靶标，定义了独特的 Eg5 抑制剂化学型。
