Synthesis and Multiplexed Activity Profiling of Synthetic Acylphloroglucinol Scaffolds

Reported here are novel formic‐acid‐mediated rearrangements of dearomatized acylphloroglucinols to access a structurally diverse group of synthetic acylphloroglucinol scaffolds (SASs). Density‐functional theory (DFT) optimized orbital and stereochemical analyses shed light on the mechanism of these rearrangements. Products were evaluated by multiplexed activity profiling (MAP), an unbiased platform which assays multiple biological readouts simultaneously at single‐cell resolution for markers of cell signaling, and can aid in distinguishing genuine activity from assay interference. MAP identified a number of SASs that suppressed pS6 (Ser235/236), a marker for activation of the mTOR and ERK signaling pathways. These results illustrate how biomimetic synthesis and multiplexed activity profiling can reveal the pharmacological potential of novel chemotypes by diversity‐oriented synthesis. Diverse synthetic acylphloroglucinol scaffolds have been produced by unprecedented cyclizations and rearrangements in formic acid, a cation‐stabilizing and nucleophilic solvent for alkenes and carbonyls. Multiplexed activity profiling (MAP) was used to evaluate multiple biological readouts at single‐cell resolution to decipher true hits from assay interference. This synthesis combined with MAP reveals the pharmacological potential of novel chemotypes produced by diversity‐oriented synthesis.