Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors

A series
of triphenylethylene bisphenol analogues of the selective
estrogen receptor modulator (SERM) tamoxifen were synthesized and
evaluated for their abilities to inhibit aromatase, bind to estrogen
receptor α (ER-α) and estrogen receptor β (ER-β),
and antagonize the activity of β-estradiol in MCF-7 human breast
cancer cells. The long-range goal has been to create dual aromatase
inhibitor (AI)/selective estrogen receptor modulators (SERMs). The
hypothesis is that in normal tissue the estrogenic SERM activity of
a dual AI/SERM could attenuate the undesired effects stemming from
global estrogen depletion caused by the AI activity of a dual AI/SERM,
while in breast cancer tissue the antiestrogenic SERM activity of
a dual AI/SERM could act synergistically with AI activity to enhance
the antiproliferative effect. The potent aromatase inhibitory activities
and high ER-α and ER-β binding affinities of several of
the resulting analogues, together with the facts that they antagonize
β-estradiol in a functional assay in MCF-7 human breast cancer
cells and they have no E/Z isomers,
support their further development in order to obtain dual AI/SERM
agents for breast cancer treatment.