$\Delta ^{9,11}$-Estrone derivatives as potential antiproliferative agents: synthesis, in vitro biological evaluation and docking studies

Abstract

A series of ${\Delta }^{{9,11}}$-estrone derivatives with A- and D-ring modifications has been synthesized and evaluated as antiproliferative agents. The cytotoxicity was assessed in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and a cell cycle distribution analysis was performed by flow cytometry. Some compounds exhibited relevant cytotoxicity, particularly ${\Delta }^{{9,11}}$-estrone, which was the most active against HepaRG cells ($\mathrm{IC}_{50} = 6.67~{{\mu }}\mathrm{M}$). Besides the relevance of the double bond in the C-ring, the presence of a 16E-benzylidene group increased the antiproliferative effect on MCF-7 and T47-D cells. Moreover, the introduction of iodine in positions 2 and 4 of estrone seemed to induce a selective cytotoxicity for HepaRG cells. Flow cytometry experiments evidenced a 34% reduction of HepaRG cell viability after treatment with ${\Delta }^{{9,11}}$-estrone and a cell cycle arrest at the $G_{0}/G_{1}$ phase. Estrogenic activity was also observed for this compound at 0.1 ${{\mu }}$M in T47-D cells, and molecular docking studies estimated a marked interaction between this compound and the estrogen receptor ${\alpha }$.

Keywords

• Estrone
• ${\Delta }^{{9,11}}$-estrone derivatives
• Antiproliferative activity
• Flow cytometry
• Docking