Design, synthesis, and in-silico study of novel triarylethylene analogs with dual anti-estrogenic and serotonergic activity

Estrogen receptor is an important target in breast cancer. Serotonin receptors (5-HT2A and 5-HT2C, in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ER alpha relative beta- galactosidase activity = 0.70), 5-HT2A (K-i = 0.97 mu M), and 5-HT2C (Ki = 3.86 mu M). It was more potent on both MCF-7 (GI(50 ) = 0.27 mu M) and on MDA-MB-231 (GI(50 )= 1.86 mu M) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF-7 and 15 times on MDA-MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in-silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ER alpha, 5-HT2A, and 5-HT2C.