Identification of biologically diverse tetrahydronaphtalen‐2‐ols through the synthesis and phenotypic profiling of chemically diverse, estradiol‐inspired compounds

Thomas Whitmarsh-Everiss, Zhou Wang, Cecilie Hauberg Hansen, Laura Depta, Elisa Sassetti, Oliver Rafn Dan, Axel Pahl, Sonja Sievers, Luca Laraia*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The combination of natural product fragments to design new scaffolds of unprecedented bioactivity is a powerful strategy for the discovery of tool compounds and potential therapeutics. However, the choice of fragments to couple and the biological screens to employ remain open questions in the field. By choosing a primary fragment comprising the A/B ring system of estradiol and fusing it to nine different secondary fragments, we were able to identify compounds that modulated four different phenotypes, including inhibition of autophagy and osteoblast differentiation, as well as potassium channel and tubulin modulation. The latter two were uncovered by using unbiased morphological profiling with the cell painting assay. The number of hits and variety in bioactivity discovered validates the use of natural product fragment recombination coupled to phenotypic screening for the rapid identification of biologically diverse compounds.
Original languageEnglish
Article numbere202200555
JournalChemBioChem
Volume24
Issue number5
Number of pages8
ISSN1439-4227
DOIs
Publication statusPublished - 2023

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