New antiestrogens from a library screen of homoallylic amides, allylic amides, and C-cyclopropylalkylamides.
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.
Janjic
Jelena M
JM
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Mu
Ying
Y
Kendall
Christopher
C
Stephenson
Corey R J
CR
Balachandran
Raghavan
R
Raccor
Brianne S
BS
Lu
Ying
Y
Zhu
Guangyu
G
Xie
Wen
W
Wipf
Peter
P
Day
Billy W
BW
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
D000577:Amides; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen