Flexible estrogen receptor modulators: Design, synthesis, and antagonisticeffects in human MCF-7 breast cancer cells

Although many series of estrogen receptor antagonists continue to be produc ed, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and th eir antiproliferative effects on human MCF-7 breast tumor cells investigate d. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introductio n of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxif en standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high bindi ng affinity. A computational study was undertaken to investigate the compou nds ' potential interactions with specific residues within the human estrog en receptor a ligand-binding domain (ER-LBD), predicting these compounds bi nd in an antiestrogenic fashion within the ER-LBD and interact with those i mportant residues previously identified in the structures of ER-LBD agonist /antagonist cocrystals. These compounds further illustrate the eclectic nat ure of the estrogen receptor in terms of ligand flexibility tolerance.