Among the newly synthesized 1,1,2,2-tetraalkyl-1,2-diphenylethanes, 1,1,2,2-tetramethyl-1,2-bis(4'-hydroxyphenyl)ethane (23) and 1,1,2,2-tetramethyl-1,2-bis(3'-hydroxyphenyl)ethane (26) were the most active compounds regarding estradiol receptor affinity, exhibiting Ka values of 0.73 X 10(8) and 0.67 X 10(8) M-1, respectively. In vivo, 23 and 26 showed only very small uterotrophic activity in the mouse. They strongly inhibited (73%) the estrone-stimulated mouse uterine growth. Tested on the 9,10-dimethyl-1,2-benzanthracene induced hormone-dependent mammary adenocarcinoma of the Sprague-Dawley rat, compounds 23 and 26 exhibited a dose-dependent inhibition of the tumor growth, having a strong effect at a dose of 20 (mg/kg)/day (compound 23).

Diastereomeric N,N'-dialkyl-1,2-bis(hydroxyphenyl)ethylenediamines (5) were synthesized and tested for their affinity for the estradiol receptor. Only the (+/-)-1,2-bis(4-hydroxyphenyl)ethylenediamines with the alkyl groups C3H7 [(+/-)-5c, Ka = 1.1 x 19(6))], C4H9 [(+/-)-5e,Ka = 3.6 x 10(6)], and C5H11 [(+/-)-5h, Ka = 2.2 x 10(6)] showed a marked affinity, which is mainly due to the (+) enantiomers [e.g., (+)-5e, Ka = 2.1 x 10(7)]. No enhancement of affinity by cyclization to imidazolidines [e.g., (+/-)-trans-7a, Ka = 1.2 x 10(7)] was observed. These compounds [e.g., (+/-)-, (+)-, and (-)-5e], which did not produce any uterine response in the mouse, were able to inhibit weakly the growth of the DMBA-induced mammary carcinoma of the rat. The inhibitory effect of (+/-)-5e against MCF-7 cells, which can be overcome by hexestrol, makes a direct antiestrogenic mode of action probable, since general cytotoxic effects and a central action could be ruled out.

The syntheses of the meso-1,2-dialkyl-1,2-bis(3'-hydroxyphenyl)ethanes [alkyl substituent: CH3 (19), C2H5 (20), C3H7 (22), C4H9 (23), i-C4H9 (24), and C5H11 (25)] and of d,l-3,4-bis(3'-hydroxyphenyl)hexane (21) are described. In vitro these compounds inhibited the [3H]estradiol receptor interaction competitively, exhibiting Ka values between 0.20 x 10(9) (20) and 0.11 x 10(6) M-1 (24). In vivo the meso compounds reduced the estrone-stimulated mouse uterine growth; the most effective compounds were 20, 22, and 23 (53, 50, and 45% inhibition, respectively). Compounds 20 and 22-24 showed weak estrogenic activity in the mouse uterine weight test and in the vaginal cornification test. Compounds 19 (NSC-297169), 20 (NSC-297170), and 22 (NSC-297171) exhibited a dose-dependent growth inhibition on the MCF-7 human breast tumor cell line (10(-6) to 10(-9) M). These compounds also showed a marked dose-dependent inhibition on the DMBA-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat corresponding to their association constants.

The syntheses of the hexestrol derivatives 3,4-bis-(3'-hydroxyphenyl)hexane (4a), 3,4-bis(4'-fluoro-3'-hydroxyphenyl)hexane (4b), 3,4-bis(3',4'dihydroxyphenyl)hexane (4c), and 3,4-bis(3',4'-diacetoxyphenyl)hexane (4d) are described. All compounds showed a marked, competitive inhibition of the estradiol receptor interaction (Ka4c greater than Ka4a greater than Ka4d greater than Ka4b). Evaluated in the mouse uterine weight test compounds 4c and 4d almost reached the estrone effect, whereas 4a and 4b did not produce full uterotrophic response. Compounds 4a--d antagonized the estrone stimulated uterine growth of the immature mouse. Compound 4a (NSC-297170) exhibited a specific, dose-related growth inhibition of the estrogen responsive MCF-7 human breast tumor cell line. Tested on the 9,10-dimethyl-1,2-benzanthracene-induced hormone-dependent mammary adenocarcinoma of the Sprague-Dawley rat all compounds showed marked inhibition of tumor growth. As in all experiments compounds 4a and 4b, which is resistant to hydroxylation in 4'-position exhibited an identical pattern of action, which is different from that shown by compound 4c, the effect of compound 4a cannot be explained by its possible catechol metabolite 4c.

The displacement of the phenolic OH-group of diethylstilbestrol into the 3,3'-position (trans-3,3'-dihydroxy-alpha, beta-diethylstilbene, compd. III) leads to a strong decrease of the estrogenic effect under conservation of the receptor affinity. In vitro, III inhibits the estradiol-receptor-interaction competitively and, in vivo, antagonises the uterotropic effect of estrone in the mouse. In tests with the DMBA-induces, hormone-dependent mammary carcinoma of the rat a dose-dependent strong decrease of tumor size and yield is achieved under the influence of III, due to the antiestrogenic properties of III. The replacement of the alpha, beta-bound ethyl groups in III by other alkyl chains leads to no further increase of the antiestrogenic and antitumor activity.