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 a 67-member library of homoallylic amides, allylic amides, and C-cyclopropylalkylamides. Several derivatives had activity comparable to that of tamoxifen. 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. © 2004 Elsevier Ltd. All rights reserved.