Synthesis and biological evaluation of a series of gem-dichlorocyclopropanes as antitumor agents.

As part of our continuous effort to produce non-steroidal antiestrogens demonstrating less intrinsic estrogenicity and greater antagonism than those in use, a series of Analog II (1,1-dichloro-2,3-diphenylcyclopropanes) derivatives was synthesized. The compounds were tested for their ability to inhibit the growth-stimulating action of estradiol in the immature mouse uterus and estrogen receptor (ER) (+) MCF-7 human breast cancer cells in vitro. Like Analog II, the derivatives were found to have no intrinsic estrogenicity (except 30) and they antagonized estradiol action less completely than the lead compound. Polarity improved the ER binding affinity of Analog II, but was quite small for all compounds, except 30, for which it was comparable to tamoxifen. Six compounds (8, 10, 14, 23, 29 and 30) demonstrated antiproliferative activity toward MCF-7 cells, in vitro, and the mean inhibition period over 6 days ranged from 20 to 37%. Only compound 30 was reversed by estradiol.