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, llepaRG, Caco-2 and NUM.) 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 llepaRG cells (IC50 = 6.67 mu 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 I lepaRG 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.