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Synthesis and Multiplexed Activity Profiling of Synthetic Acylphloroglucinol Scaffolds
Author(s) -
Boyce Jonathan H.,
Reisman Benjamin J.,
Bachmann Brian O.,
Porco John A.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202010338
Subject(s) - chemistry , mapk/erk pathway , biomimetic synthesis , computational biology , combinatorial chemistry , profiling (computer programming) , signal transduction , biochemistry , biology , computer science , operating system
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.