The natural product ferutinin was shown to act as an agonist to estrogen receptor ERαand agonist/antagonist to ERβfeaturing a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for theirin vitroantiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c′ exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1μm. Docking simulation of 3c′ in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c′ binds as an antagonist to ERαprotein while ferutinin acts as an agonist.
A series of novel ferutinin derivatives were synthesized, biologically evaluated and tested for their in silico targets, the estrogen receptors α and β. Two compounds exhibited improved cytotoxic activities on the proliferation of estrogen-dependent and -independent breast cancer cell lines, as compared to the parent compound. Molecular docking studies and functional assay on ferutinin and its potent analogue showed that the cytotoxic effect in estrogen-dependent cells may be correlated to the antagonist potential of the new compound towards ERα protein.