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.

Automated summary

This study reports novel rearrangements of acylphloroglucinols mediated by formic acid to access diverse synthetic acylphloroglucinol scaffolds, with insights on the mechanism provided by Density-functional theory (DFT) analysis. Evaluation of products using multiplexed activity profiling (MAP) identified SASs that suppressed pS6 (Ser235/236) markers of mTOR and ERK signaling pathways activation. These results demonstrate the pharmacological potential of novel chemotypes through biomimetic synthesis and multiplexed activity profiling.