Ethyl side-chain modifications in novel flexible antiestrogens--design, synthesis and biological efficacy in assay against the MCF-7 breast tumor cell line.

To examine the efficacy of ethyl side-chain modifications in a family of flexible non-steroidal modulators of the estrogen receptor, a series of novel compounds was prepared and their antiproliferative effects on human MCF-7 breast tumor cells evaluated. These flexible antiestrogens consisted of members wherein the ethyl portion of the parent compound, a flexible analogue of tamoxifen, had been modified so as to introduce halogens or a nitro group, or to extend the side-chain length from ethyl to propyl or butyl. The compounds demonstrated potency at low micromolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low associated cytotoxicity. Tested compounds exhibited nanomolar binding affinity (Ki) for the estrogen receptor (ER) as determined through displacement of radiolabelled estradiol. Semiempirical calculations predict an inherent lower oxidative potential at the allylic position, similar to that calculated for the established analogue toremifene, indicating a lesser propensity of such compounds towards metabolic oxidative carbocation generation and consequent DNA adduct formation. Computational studies predict these compounds to bind in a typical estrogen antagonist mode within the ER-ligand binding domain (LBD). Ethyl side-chain modification in this compound class is well tolerated within the ER and is not detrimental to compound efficacy, with additional potential anti-carcinogenic properties imbued to the molecule.