Tamoxifen‐Based Dimers: Design, Synthesis, Cell Viability Evaluation on Breast Cancer Cells, and Computational Insights

ABSTRACT Tamoxifen (TMX) resistance presents a significant challenge in the treatment of ER+ breast cancer. In this study, four novel tamoxifen‐based dimers were synthesized and evaluated for their antitumor activities. Among these, ( Z,Z )‐ 1 exhibited potent antiproliferative effects in ER+ cells, demonstrating selective toxicity toward cancer cells over normal cells. ( Z,Z )‐ 1 significantly outperformed tamoxifen with IC 50 values of 9.18 μM (24 h) and 6.86 μM (48 h) against MCF‐7 cells. Additionally, it showed greater selectivity toward ER+ breast cancer cells compared with both triple‐negative cancer cells and non‐cancerous cells. Mechanistic studies indicated that ( Z,Z )‐ 1 induces apoptosis in MCF‐7 cells through a cell‐cycle‐independent mechanism, unlike TMX, which arrests cells at the G0/G1 phase. These findings suggest that ( Z,Z )‐ 1 may be a promising candidate for further development as an alternative to tamoxifen therapy in ER+ breast cancer treatment. The docking studies revealed that ( Z,Z )‐ 1 exhibits the strong binding affinity to ERα, highlighting its potential as a promising therapeutic candidate for ER+ breast cancer treatment.