Deoxybenzoins (1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone) are possible precursors or metabolites of isoflavanones which may have xenoestrogenic potential on estrogen receptor (ER). In this study we evaluated three 2'-substituted deoxybenzoin derivatives for their estrogenic effect based upon their ability to affect the proliferation of ERα(+) MCF7 cells, ERβ(+) PC3 cells and Hep2 cells stably transfected and expressing either ERα or ERβ. These compounds designated as CMPD3, CMPD6 and CMPD9 had -COOH, -(CH(2))(4)-CH(3) and -CH(3) substitutions, respectively on the 2'-position of the 2,4-dihydroxyphenyl ring of deoxybenzoin. We found that all three compounds increased the proliferation of ERα(+) MCF7 cells (EC(50)~1-12 μM) and ERα(+) Hep2 cells, while causing apoptosis in ERβ(+) PC3 cells (IC(50)~1-5 μM) and ERβ(+) Hep2 cells. The compounds also up-regulated the expression of estrogen sensitive genes, trefoil factor 1 (TFF1, previously known as pS2) and cathepsin-D (CTSD), in these cells. We performed in vitro ER transcription activation assays using Hep2 cells transiently co-transfected with estrogen response element driven luciferase and either ERα or ERβ vectors to ascertain the mechanism of action of these compounds through the 'classical' genomic pathway of estrogenic activity and to determine their ER subtype selectivity. Molecular docking of the compounds with the Ligand Binding Domain of ERα and ERβ showed similar docking scores (Glidescores of -6.5 to -8.5 kcal/mol) indicating that these compounds were ligands of both ERα and ERβ with similar affinity.
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