Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA, 02215, USA.
Current Address: Department of Pharmaceutical Chemistry, University of California, San Francisco, 555 Mission Bay Blvd S., San Francisco, CA, 94158, USA.
Angew Chem Int Ed Engl. 2021 Jan 18;60(3):1263-1272. doi: 10.1002/anie.202010338. Epub 2020 Nov 30.
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.
报告了一种新型的甲酸介导的去芳构化酰基间苯三酚重排反应，可获得结构多样的合成酰基间苯三酚骨架（SASs）。密度泛函理论（DFT）优化的轨道和立体化学分析阐明了这些重排反应的机理。通过多重活性分析（MAP）对产物进行评估，MAP 是一种在单细胞分辨率下同时检测多种生物学读数的无偏平台，用于检测细胞信号的标记物，可帮助区分真实活性和检测干扰。MAP 鉴定出了一些抑制 pS6（Ser235/236）的 SASs，pS6 是 mTOR 和 ERK 信号通路激活的标志物。这些结果说明了仿生合成和多重活性分析如何通过多样性导向合成揭示新型化学型的药理学潜力。
