Study of tamoxifen derived perfluoroalkylated olefins in breast cancer treatment

Estrogen-responsive breast cancer has been treated with tamoxifen since 1998, yet challenges such as limited selectivity and emerging resistance remain significant hurdles to improving therapeutic outcomes. In recent years, the incorporation of fluorine atoms in the structure of potential drugs has gained importance due to their unique properties. Perfluoroalkyl chains, known for their chemical inertness and ability to target estrogen, offer promising modifications to improve treatment efficacy. In this study, we evaluated the biological activity of 21 perfluoroalkylated tamoxifen derivatives, synthesized under mild conditions with high stereoselectivity. Seven of these compounds exhibited superior cytotoxic and selectivity activity against estrogen receptor-positive breast cancer cells (MCF-7), with IC50 values of 10.68–18.18 nM compared to 29.41 nM for 4-hydroxytamoxifen, which is used in standard therapy. Preliminary mechanism-of-action studies, supported by siRNA knockdown of ESR1 (the estrogen receptor gene), revealed that the compounds act through a similar mechanism to tamoxifen, further confirming their potential as next-generation therapeutic agents for estrogen receptor-positive breast cancer. • Tamoxifen has been a standard treatment for estrogen-responsive breast cancer since 1998, but challenges such as resistance and lack of selectivity remain. • Perfluoroalkyl chains, known for their inertness and ability to target estrogen receptors, were used to modify tamoxifen to improve its efficacy. • A series of 21 perfluoralkylated tamoxifen derivatives were synthesized and biologically tested. • Seven derivatives demonstrated superior cytotoxicity and selectivity for estrogen-positive breast cancer cells (MCF-7) compared to the parent compound, with IC50 values ranging from 10.68 to 18.18 nM, significantly better than 4-hydroxytamoxifen (IC50 29.41 nM). • Mechanistic studies revealed that these compounds exhibited similar action mechanisms to tamoxifen, suggesting they may overcome resistance while improving selectivity.