An Indole Dearomatization Strategy for the Synthesis of Pseudo-Natural Products.

The indole moiety is a privileged fragment that frequently populates existing bioactive compound collections. We describe the development of an indole-dearomatization sequence and its application for library expansion of a collection of indole-containing pseudo-NPs. The resulting compounds are topologically distinct from the original compound class. Phenotyping by means of the cell painting assay initially indicated that the dearomatized compounds are morphologically different than the original pseudo-NP compound class and guiding NPs. However, analysis by means of a new sub-profile analysis of the same cell painting assay data indicated that similar morphologies persisted throughout the compound classes. Further biological studies supported the findings of the sub-profile analysis and highlights its potential to more effectively characterize novel compounds. The biological findings suggest that a plethora of indole-dearomatization reactions could be applied to existing indole-containing compound collections to rapidly access new biologically relevant scaffolds.