Design, semisynthesis and estrogenic activity of lignan derivatives from natural dibenzylbutyrolactones

Abstract

Based on molecular docking studies on the ERα, a series of lignan derivatives (3-16) were designed and semisynthesized from the natural dibenzylbutyrolactones bursehernin (1) and matairesinol dimethyl ether (2). To examine their estrogenic and antiestrogenic potencies, the effects of these compounds on estrogen receptor element (ERE) driven reporter gene expression, and viability, in human ER+ breast cancer cells were evaluated. Lignan compounds induced ERE driven reporter gene expression with very low potency compared to pure agonist E2. However, co-incubation of 5 µM of lignan derivatives 1, 3, 4, 7, 8, 9, 11, 13 and 14 with increasing concentrations of E2 (from 0.01 pM to 1 nM) reduced both, potency and efficacy of pure agonist. The binding to the rhERα-LBD was validated by TR-FRET competitive binding assay and lignans bound to the rhERα with IC50 values from 0.16 µM (compound 14) to 6 µM (compound 4). Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations for compound 14 were carried out to get deeper in the binding mode interactions. Finally, in silico ADME predictions indicated that the most potent lignan derivatives exhibited good drug-likeness.