title: New antiestrogens from a library screen of homoallylic amides, allylic amides, and C-cyclopropylalkylamides.
abstract: A new structural scaffold for antiestrogens was identified from the cell-based screening of transcriptional regulation properties of a 67-member library of homoallylic amides, allylic amides, and C-cyclopropylalkylamides. C-Cyclopropylalkylamide 3a (O-ethyl-N-{2-[(1S*,2R*)-2-{(R*)-[(diphenylphosphinoyl)amino](phenyl)methyl}cyclopropyl]ethyl}-N-[(4-methylphenyl)sulfonyl]carbamate) had antagonistic activity similar to that of tamoxifen and was further evaluated. Compound 3a inhibited estradiol-induced proliferation of the ER-positive MCF-7 cells but had no effect on ER-negative MDA-MB231 human breast cancer cells. Furthermore, high micromolar concentrations of 3a exhibited minimal cytotoxicity to the ER-negative line. The biological activities of the enantiomers of 3a did not differ from one another nor from that of racemic 3a.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Jelena M
authors.initials: JM
authors.lastname: Janjic
authors.forename: Ying
authors.initials: Y
authors.lastname: Mu
authors.forename: Christopher
authors.initials: C
authors.lastname: Kendall
authors.forename: Corey R J
authors.initials: CR
authors.lastname: Stephenson
authors.forename: Raghavan
authors.initials: R
authors.lastname: Balachandran
authors.forename: Brianne S
authors.initials: BS
authors.lastname: Raccor
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen