2-Alkyl-substituted 1,1-bis(4-acetoxyphenyl)-2-phenylethenes. Estrogen receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activity

Journal of Medicinal Chemistry
1986.0

Abstract

1,1-Bis(4-acetoxyphenyl)-2-phenylethenes that are substituted with H, CH3, C2H5, n-C3H7, i-C3H7, or CH2CF3 in position 2 were synthesized in order to study the influence of the alkyl side chain on estradiol receptor affinity, estrogenic and antiestrogenic properties, and inhibition of the hormone-dependent MXT mammary carcinoma of the mouse. Furthermore, the double bond of 1,1-bis(4-acetoxyphenyl)-2-phenylbut-1-ene was hydrogenated or epoxidated to yield the corresponding ethane and oxirane derivative. Compounds 14 (R = H), 15 (R = CH3), and 16 (R = C2H5) had the best binding affinities. Lengthening the side chain, hydrogenation, or epoxidation decreased the RBA values. In the immature mouse assay, 15 (R = CH3) and 19 (R = CH2CF3) had the highest uterotrophic activity. There was no correlation between receptor affinity and estrogenic properties. Compounds 14 (R = H), 17 (R = n-C3H7), the ethane 20, and the oxirane 21 had some antiuterotrophic activity in a low dosage. The MXT tumor was best inhibited by compounds 15 (R = CH3), 16 (R = C2H5), and 18 (R = i-C3H7) without significant elevation of the uterine weight determined at the end of the experiment. The antitumor effect of 15, 16, and 18 was significantly better than that of tamoxifen. In this series, a certain estrogenic potency in the immature mouse test seems to be necessary for a good antitumor activity, as all compounds with antiuterotrophic and low uterotrophic properties did not exert any significant tumor-inhibiting effect.

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