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Tamoxifen-Based Dimers: Design, Synthesis, Cell Viability Evaluation on Breast Cancer Cells, and Computational
Berrak Ertugrul1, Abdulmelik Aytatli2,3, Omer Faruk Karatas2,3
1Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum, Türkiye.
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 IC50 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.
Insights
A new tamoxifen-based compound, (Z,Z)-1, shows potent and selective antitumor activity against estrogen receptor-positive (ER+) breast cancer cells. It effectively induces apoptosis and may offer a promising alternative to tamoxifen therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Tamoxifen resistance is a major obstacle in treating estrogen receptor-positive (ER+) breast cancer.
- Developing novel therapeutic agents is crucial to overcome treatment resistance.
Purpose of the Study:
- To synthesize and evaluate novel tamoxifen-based dimers for antitumor activity.
- To investigate the efficacy and selectivity of (Z,Z)-1 as a potential breast cancer therapeutic.
Main Methods:
- Synthesis of four novel tamoxifen-based dimers.
- In vitro antiproliferative assays using ER+ breast cancer cells (MCF-7), triple-negative cancer cells, and non-cancerous cells.
- Apoptosis induction studies and cell cycle analysis.
- Molecular docking studies with estrogen receptor alpha (ERα).
Main Results:
- (Z,Z)-1 demonstrated significant antiproliferative effects against ER+ cells, outperforming tamoxifen.
- Selective toxicity was observed for (Z,Z)-1 towards cancer cells over normal cells.
- (Z,Z)-1 induced apoptosis via a cell-cycle-independent mechanism, distinct from tamoxifen's G0/G1 arrest.
- Docking studies confirmed strong binding affinity of (Z,Z)-1 to ERα.
Conclusions:
- (Z,Z)-1 is a potent and selective agent against ER+ breast cancer.
- Its distinct mechanism of action and strong ERα binding suggest potential as an alternative to tamoxifen.
- (Z,Z)-1 warrants further investigation for clinical development in ER+ breast cancer treatment.
