SYNTHESIS AND BIOLOGICAL EVALUATION OF BASIC SIDE-CHAIN DERIVATIVES OF ANALOG-II AS PURE ANTIESTROGENS AND ANTITUMOR AGENTS

In an effort to prepare effective non-steroidal antiestrogens without intrinsic estrogenicity and with greater antagonism than those of the triarylethylenes (tamoxifen; TAM) four N-substituted o-2-[4-(2-aminoet hoxy)phenyl]-3-phenylcyclopropane derivatives of the antiestrogen, Ana log II, in which the basic side chains contain cyclic (piperidino and piperazino) and non-cyclic (dimethyl amino and diethyl amino) moieties , were synthesized. These compounds were prepared from an intermediate methanesulfonyloxyethoxy side chain ester of 1,1-dichloro-2,3-cis-dip henylcyclopropane using their respective side chain bases in triethyla mine and acetonitrile. The gem-dichloro-cis-diarylcyclopropane derivat ives were tested for their ability to inhibit the growth-stimulating e ffect of estradiol on immature mouse uteri and the growth of estrogen receptor (ER)-positive MCF-7E3, ER-negative MDA-MB-231. and the ER-pos itive MCF-7LY2 antiestrogen-resistant breast cancer cells in culture. The introduction of the various aminoethoxy side chains into Analog II did not improve its ER-binding affinity. Like Analog II, the derivati ves did not exhibit any intrinsic estrogenicity, and compounds 9 and 1 0 antagonized estradiol action more completely than the parent compoun d. None of the compounds potentiated the uterine weight gain from the stimulating dose of estradiol (0.03 mu g) Derivatives 9 (150 mu g), 10 (150 mu g) and 11 (150 mu g) had uterine mean weights significantly b elow the estradiol-treated group, and were better antagonists than Ana log II and MER25 at the same concentrations. All compounds exhibited a statistically significant (P < 0.01) reduction in control growth (ant itumor activity) from 0.01 to 10 nM concentration in the MCF-7E3 cells . At 10 nM concentration, 8 (66%) and 9 (64%) had the greater antitumo r activity over 10 (58%) and 11 (58%). No activity in this cell line w as observed for Analog II, TAM and ICI 182,780. Antitumor action was a lso demonstrated in the MDA-MB-231 cells for all derivatives at 1.0 mu M dose, with 9 having the greatest (27%) inhibition of control growth , followed by 8 (20%), 10 (18%) and 11 (12%). Analog II and ICI 182,78 0 had no antitumor activity in this cell line, while TAM exhibited onl y 8% inhibition. In the MCF-7E3 cell line at 1.0 mu M, 9 exhibited 86% inhibition of the estradiol-stimulated growth (antiestrogenic activit y), followed by 8 (64%), 10 (52%) and 11 (21%). Analog II produced 10% inhibition, while TAM and ICI 182,780 produced 75 and 99% inhibition, respectively. Compounds 8, 9 and 10 have the potential to be useful i n the treatment of hormone-unresponsive as well as hormone-responsive breast cancer.