title: Antiestrogens. 3. Estrogen receptor affinities and antiproliferative effects in MCF-7 cells of phenolic analogues of trioxifene, [3,4-dihydro-2-(4- methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]- phenyl]methanone.
abstract: Benzothiophenes 3 and 4, derived from the acrylophenone antiestrogen trioxifene (2), are characterized by high estrogen receptor (ER) affinity and low residual estrogenicity compared to tamoxifen (1a). In order to characterize further the growth suppression mechanism for these structural types we have prepared structural variants of 2 bearing hydroxy groups positioned to maximize ER affinity. Thus, dihydronaphthalenes 5 and 6 and benzofluorenes 7 and 8 were prepared and studied in MCF-7 human breast cancer cells, in comparison with 3 and 4. All compounds were powerful suppressants of cell growth, with 50% inhibition ranging from 4.5 to 160 nM. Greatest potency was seen with diphenols 6 and 8. These compounds had intracellular ER affinities ranging from 0.2 to 4.1% of that of estradiol, suggestive of a potential for partial agonist effects. Simultaneous exposure of cells to 0.1 microM concentrations of estradiol and 3 or 4 did not affect the degree of growth inhibition seen with 0.1 microM 3 or 4 alone. Partial reversal of inhibition occurred when 0.1 microM 5-8 were each accompanied by 0.1 microM estradiol. Under these conditions complete reversal of growth inhibition has been found with 1a, 1b, and other triarylethylenes. Calmodulin, a putative target for triarylethylenes, and which is antagonized by 1a, was shown to interact weakly with 7 and 8 and not at all with 3-6. These results suggest that MCF-7 cell growth suppression by 3-8 may be due to interaction with unidentified receptors besides ER and extend earlier findings indicating that events occurring after interaction of these compounds with ER differ from those of triarylethylene antiestrogens.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: C D
authors.initials: CD
authors.lastname: Jones
authors.forename: L C
authors.initials: LC
authors.lastname: Blaszczak
authors.forename: M E
authors.initials: ME
authors.lastname: Goettel
authors.forename: T
authors.initials: T
authors.lastname: Suarez
authors.forename: T A
authors.initials: TA
authors.lastname: Crowell
authors.forename: T E
authors.initials: TE
authors.lastname: Mabry
authors.forename: P C
authors.initials: PC
authors.lastname: Ruenitz
authors.forename: V
authors.initials: V
authors.lastname: Srivatsan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002147:Calmodulin; D004965:Estrogen Antagonists; D010636:Phenols; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; C014934:trioxifene