title: Antiestrogenically active 1,1,2-tris(4-hydroxyphenyl)alkenes without basic side chain: synthesis and biological activity.
abstract: C2-Alkyl substituted derivatives of the 1,1,2-tris(4-hydroxyphenyl)ethene 3a (alkyl = Me (3b), Et (3c), Prop (3d), But (3e)) were synthesized by reaction of 1,2-bis(4-methoxyphenyl)ethanone with the appropriate alkyl halide, followed by a Grignard reaction with 4-methoxyphenylmagnesium bromide, dehydration with phosphoric acid or hydrobromic acid, and ether cleavage with BBr(3). The compounds were tested for estrogen receptor (ER) binding affinity in a competition experiment with radio labeled estradiol ([(3)H]-E2) and for gene activation on the ER-positive MCF-7-2a cell line. All compounds showed high receptor binding affinity (RBA-value: 3b (52.1%) > 3a (45.5%) > 3c (29.6%) > 3d (4.03%) > 3e (0.95%)). The tests on hormone dependent MCF-7-2a breast cancer cells, stably transfected with the plasmid ERE(wtc)luc, revealed that all 1,1,2-tris(4-hydroxyphenyl)ethenes antagonized the effect of 1 nM estradiol (E2). The compounds 3b (IC(50) = 15 nM) and 3c (IC(50) = 10 nM) were equal in their effects to 4-hydroxytamoxifen (4OHT) (IC(50) = 7 nM). Agonistic effects were low. Only 3a and 3b activated the luciferase expression (relative activation at 1 microM: 3a 60%; 3b 35%). Despite their highly antagonistic potency, the 1,1,2-tris(4-hydroxyphenyl)ethenes showed only low cytotoxic properties on the hormone sensitive MCF-7 cell line.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Königin-Luise-Strasse 2 + 4, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lubczyk
authors.forename: Helmut
authors.initials: H
authors.lastname: Bachmann
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001943:Breast Neoplasms; D002417:Cattle; D003600:Cytosol / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000648:ultrastructure
chemical_list: D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D005030:Ethylenes; D010636:Phenols; D011960:Receptors, Estrogen