Identification of Biologically Diverse Tetrahydronaphthalen-2-ols through the Synthesis and Phenotypic Profiling of Chemically Diverse, Estradiol-Inspired Compounds

Combining natural product fragments to design new scaffolds with 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 containing 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: 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 a cell-painting assay. The number of hits and variety in bioactivity discovered validates the use of recombining natural product fragments coupled to phenotypic screening for the rapid identification of biologically diverse compounds.

Automated summary

Combining natural product fragments to design new scaffolds with unprecedented bioactivity is an effective strategy for discovering useful compounds for tools and potential therapeutics. However, the choice of fragments to couple and the biological screens to use still remain unanswered questions. In this study, by combining a primary fragment containing the A/B ring system of estradiol with nine different secondary fragments, compounds that modulated four different phenotypes were identified. The use of unbiased morphological profiling with a cell-painting assay also revealed additional phenotypes that were not previously known. The discovery of a variety of biologically active compounds demonstrates the value of recombining natural product fragments with phenotypic screening for rapid compound identification.