Synthesis and Multiplexed Activity Profiling of Synthetic Acylphloroglucinol Scaffolds

Abstract

Reported here are novel formic-acid-mediated rearrangements of dearomatized acylphloroglucinols to access as tructurally diverse group of synthetic acylphloroglucinol scaffolds (SASs). Density-functional theory (DFT) optimized orbital and stereochemical analyses shed light on the mechanism of these rearrangements.P roducts 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 assayi nterference. MAP identified an umber of SASs that suppressed pS6 (Ser235/236), amarker for activation of the mTOR and ERK signaling pathways.T hese results illustrate howb iomimetic synthesis and multiplexed activity profiling can reveal the pharmacological potential of novel chemotypes by diversityoriented synthesis.