Effect of N,N'-diethyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines on the DMBA-induced mammary carcinoma of the rat

The syntheses and estrogen receptor affinities of meso- and (~)-N,N’-dialkyl-1,2-bis(2,6-dichloro-4-hydroxypheny1) ethylenediamines (2) are described. They show high binding affinities in both diastereomeric forms but with a preference for the meso isomer, reaching a RBA value of 8.6 (meso-2b; 17@-estradiol=1 00). Both stereoisomers of 2b exhibit a strong inhibitory effect on the 7,12-dimethylbenz[a]anthracene( DMBA) induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat, reducing the tumor area by 74 (meso-2b) and 24% [(*)-2b], respectively, after 4 weeks administration of 6 X 6 (mg/kg)/week. The high uterotrophic potency makes a mode of action likely which corresponds to the effect of high doses of estrogens

Effect of N,N'-diethyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines on the 7,12-dimethylbenz[a]anthracene-induced mammary carcinoma of the rat.

The syntheses and estrogen receptor affinities of meso- and (+/-)-N,N'-dialkyl-1,2-bis(2,6-dichloro-4-hydroxypheny)ethylenediamines (2) are described. They show high binding affinities in both diastereomeric forms but with a preference for the meso isomer, reaching a RBA value of 8.6 (meso-2b; 17 beta-estradiol = 100). Both stereoisomers of 2b exhibit a strong inhibitory effect on the 7,12-dimethylbenz[alpha]anthracene (DMBA) induced hormone-dependent mammary carcinoma of the Sprague-Dawley rat, reducing the tumor area by 74 (meso-2b) and 24% [(+/-)-2b], respectively, after 4 weeks administration of 6 x 6 (mg/kg)/week. The high uterotrophic potency makes a mode of action likely which corresponds to the effect of high doses of estrogens

Entwicklungsstrategien fur Arzneistoffe zur Therapie hormonabhangiger Tumoren

New strategies of drugs for treatment of hormone-related tumors

2-(Hydroxyphenyl)indoles: a new class of mammary tumor inhibiting compounds

1-Alkyl-4-chloro-2-(2,6-dichloro-4-hydroxyphenyl)-6-hydroxyindoles (4, alkyl = CH3, C2H5, C3H7) were synthesized by thermolysis of the corresponding N,N'-dialkyl-1,2-diphenylethylenediamines and subsequent ether cleavage. They showed an affinity for the estrogen receptor (1% of 17 beta-estradiol) and inhibited the growth of the 9,10-dimethyl-1,2-benz[a]anthracene (DMBA) induced mammary carcinoma of the Sprague-Dawley (SD) rat. The best result was obtained by the ethyl compound (4b), which reduced the original tumor area by 50% after 4 weeks administration of 6 X 18 (mg/kg)/week. Since 4a and 4b show uterotrophic activity and cytostatic effects against hormone-independent cells, a dual mode of action has to be considered for the tumor inhibition

Estrogenic and antiestrogenic activities of 2,4-diphenylfuran-based ligands of estrogen receptors α and β

The estrogen receptor (ER) exists in two isoforms ERα and ERβ with a different distribution in the body and different functions which are not clearly identified yet. Thus, it is desirable to have both agonists and antagonists with selectivity for one or the other ER isoform available. In a previous study we showed that 2,5-diphenylfurans can be converted into pure antiestrogens with preference for ERα. When the arrangement of the phenyl rings was altered to a 2,4-substitution, the alpha-selectivity was lost as demonstrated by comparative assays using recombinant human ERα and ERβ. 3,5-Dialkyl-2,4-bis(4-hydroxyphenylfurans) were shown to act as agonists with preference for ERβ. Replacement of one of the alkyl groups by the [(pentylsulfanyl)propyl]aminohexyl side chain afforded estrogen antagonists without receptor selectivity. These derivatives were characterized as pure antiestrogens in transcription and proliferation assays in ER+ MCF-7 breast cancer cells. The most potent antagonists displayed IC50 values of ca. 20 nM (fulvestrant 4 nM). The data showed that the 2,4-arrangement of the phenyl rings in the furan structure increases the binding affinity for ERβ in comparison to the isomeric 2,5-diphenylfurans but does not lead to a pure antagonist with selectivity for ERβ

3-Alkyl-2-phenylbenzo[b]thiophenes: nonsteroidal estrogen antagonists with mammary tumor inhibiting activity

A number of 2-(4-hydroxyphenyl)benzo[b]thiophenes with a hydroxy group in position 5 or 6 and a short alkyl group at C-3 were synthesized and studied for their estrogen receptor affinities. Relative binding affinities (RBA) for the calf uterine estrogen receptor ranged from 3 to 60 (17 beta-estradiol = 100). The highest RBA values were found with ethyl derivatives [3 (5-OH): 60; 7 (6-OH): 28]. In accord with their receptor affinity, all benzothiophenes exhibited endocrine activity in the immature mouse uterine weight test. At doses of 0.25-7.0 mg/kg body weight, they showed partial estrogen antagonism and usually weak estrogenic effects. All compounds entered tests with hormone-sensitive human MCF-7 breast cancer cells. At concentrations of 1 microM and higher, most of the derivatives displayed significant inhibition of cell growth. These results prompted us to test them in vivo for cytostatic activity using hormone-dependent MXT mouse mammary tumors. The 5-hydroxy derivatives 3 and 4 strongly inhibited the growth of these tumors. After 4 weeks of treatment with 3 x 4.2 mg/kg of compound 3, the average tumor weight was reduced by 83% vs control (tamoxifen at equimolar dose: 74%). The 6-hydroxy derivative 7 required higher doses (25 mg/kg) to give rise to the same antitumor effect. At the end of therapy, no increase of uterine weight due to an estrogenic effect was observed. We assume therefore that the antineoplastic activity of these compounds in this tumor model is due mainly to their estrogen antagonism