Potent genistein derivatives as inhibitors of estrogen receptor alpha-positive breast cancer

The estrogen receptor (ER) is a major target for the treatment of breast cancer cells. Genistein, a soy isoflavone, possesses a structure similar to estrogen and can both mimic and antagonize estrogen effects although at high concentrations it inhibits breast cancer cell proliferation. Hence, to enhance the anticancer activity of genistein at lower concentrations, we have synthesized seven structurally modified derivatives of genistein (MA-6, MA-8, MA-11, MA-19, MA-20, MA-21 and MA-22) based on the structural requirements for an optimal anticancer effect. Among those seven, three derivatives (MA-6, MA-8 and MA-19) showed high antiproliferative activity with IC(50) levels in the range of 1-2.5 mu M, i.e., at much lower concentrations range than genistein itself, in three ER-positive breast cancer cell lines (MCF-7, 21PT and T47D) studied. In our analysis, we noticed that at IC(50) concentrations, the MA-6, MA-8 and MA-19 genistein derivatives induced apoptosis, inhibited ER alpha messenger RNA expression and increased the ratio of ER beta to ER alpha levels in a manner comparable to the parent compound genistein. Of note, these three modified genistein derivatives exerted their effects at concentrations 10-15 times lower than the parent compound, decreasing the likelihood of significant ER alpha pathway activation, which has been a concern for genistein. Hence, these compounds might play a useful role in breast cancer chemoprevention.