1,1,2-Triphenylbut-1-enes: relationship between structure, estradiol receptor affinity, and mammary tumor inhibiting properties

Abstract

1,1,2-Triphenylbut-1-enes, which are substituted with acetoxy groups on one, two, or three aromatic rings in the para and/or meta positions, were synthesized. The identity of the occurring E and Z isomers were established by 1H NMR spectroscopy. A study on structure-activity relationships was carried out with regard to estradiol receptor affinity and to inhibiting effects on the growth of a postmenopausal human mammary carcinoma implanted in nude mice. The para-substituted compounds generally exhibited a higher receptor affinity and a better antitumor activity than the corresponding meta-substituted ones. The E isomers were superior to the respective Z isomers in those two properties. The tumor-inhibiting effect of the mono- and disubstituted compounds was better than that of the trisubstituted ones. Except for the trisubstituted compounds, they all show a good correlation between estradiol receptor affinity and antitumor activity. One of the compounds was also tested on the 9,10-dimethylbenz[a]-anthracene-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat, and the results corresponded to those obtained in the xenograft tumor.

Oestrogenic and antioestrogenic actions in a series of triphenylbut‐1‐enes: modulation of prolactin synthesis in vitro

“…These compounds were selected because the oestrogen triphenylbutene forms the nucleus of the antioestrogen tamoxifen. Several of the compounds have previously been screened for antitumor activity against human breast cancers transplanted into athymic mice (Schneider et al, 1982). However, precise studies of structureactivity relationships are complex in vivo because of log concentration oestradiol (mol l-') Figure 6 Competitive reversal of the inhibitory action of bis,para-acetoxy-phenyl-2-phenyl-but-l-ene on oes- Although this is a possibility in vitro the contrasting pharmacology of bis 1,1. para-hydroxyphenyl-2-phenyl-but-l-ene and bis l,l-para-acetoxy-phenyl-2-phenyl-but-l-ene argues against the suggestion.…”

“…The derivatives of 1,1 ,2-triphenylbut-l-ene were synthesized and characterized at the University of Regensburg as previously described (Schneider et al, 1982 triphenylbut-l-ene caused an increase in the RBA compared with mono-para acetoxy substitution (Figure 1). Receptor affinity was further improved with bis 1,1 phenolic substitution.…”

“…The derivatives of 1,1 ,2-triphenylbut-l-ene were synthesized and characterized at the University of Regensburg as previously described (Schneider et al, 1982 The EC50 is calculated as the concentration (M) of a compound to produce prolactin synthesis that is 50% of the maximum. WI.…”

Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells

“…FBS was from HyClone (Logan, UT) and cultureware was from Corning-Costar (Cambridge, MA). Tamoxifen analogs were prepared by Dr. McCague at the Institute for Cancer Research as follows: N,N-dimethyl-2-[(4-phenylmethyl) phenoxy]ethanamine (Rowlands et al, 1990), the diethyl analog of tamoxifen (Jarman and McCague, 1985), and triphenylbut-1-ene (Schneider et al, 1982). 3-OH-tamoxifen (droloxifene) was a gift from Pfizer Central Research (Groton, CT) and 4-OH-tamoxifen was a gift from Dr. D. Salin-Drouin (Besins Iscovesco, Paris, France).…”

Antitumor steroids: 2. Synthesis and biological activity of 11α-hydroxyestra-1,3,5,(10)-triene derivatives with bis-(2-chloroethyl)amino-containing substituents

“…The interaction with estrogen receptors of the rat uterus was studied in vitro by means of competitive binding analysis [10,11] and evaluated as the relative binding activity (RBA, %) in comparison with that of estradiol.…”