Design, synthesis and biochemical evaluation of estrogen receptor ligand conjugates as tumour targeting agents

The estrogen receptors (ERα and ERβ), are ligand inducible nuclear receptors which play a key role in many cellular functions through specific gene expression regulation. The estrogen receptor is regarded as an attractive therapeutic target for hormone-dependent breast cancers. The antiestrogen drug tamoxifen is useful in the treatment of breast cancer. To develop new ER targeting agents as probes of estrogen receptor action, the synthesis and preliminary biochemical evaluation of five structurally varied estrogen receptor ligand conjugates containing the tamoxifen metabolite endoxifen are now reported. These structurally varied conjugates bind to the estrogen receptor (commonly overexpressed in breast cancer cells) and contain DNA alkylating, aromatase inhibitor and COX2 inhibitor moieties. The ER targeting group endoxifen (E/Z 4-hydroxy-N-desmethyltamoxifen) was selected for its ability to bind to the estrogen receptor. Compound 11 exhibited moderate antiproliferative activity IC ₅₀ = 1.64 μM in MCF-7 breast cancer cells, while compound 9b demonstrated the most potent ER binding effects with IC ₅₀ values of 35.6 nM(ERα), 19.5 nM(ERβ).