title: Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens.
abstract: A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.
authors.affiliation: Medicinal Chemistry/Pharmacodynamics Section, College of Pharmacy, University of Oklahoma Health Science Center, Oklahoma City 73190.
authors.forename: B W
authors.initials: BW
authors.lastname: Day
authors.forename: R A
authors.initials: RA
authors.lastname: Magarian
authors.forename: P T
authors.initials: PT
authors.lastname: Jain
authors.forename: J T
authors.initials: JT
authors.lastname: Pento
authors.forename: G K
authors.initials: GK
authors.lastname: Mousissian
authors.forename: K L
authors.initials: KL
authors.lastname: Meyer
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen