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

Author:

Mostafa Tammy1,Albeir Miriam1,Wober Jannette2,Abadi Ashraf1,Salama Ismail3,Ahmed Nermin S.1ORCID

Affiliation:

1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology German University in Cairo Cairo Egypt

2. Institute of Zoology, Faculty of Biology Technische Universität Dresden Dresden Germany

3. Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy Suez Canal University Ismailia Egypt

Abstract

AbstractEstrogen 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 (ERα relative β‐ galactosidase activity = 0.70), 5‐HT2A (Ki = 0.97 µM), and 5‐HT2C (Ki = 3.86 µM). It was more potent on both MCF‐7 (GI50 = 0.27 µM) and on MDA‐MB‐231 (GI50 = 1.86 µM) 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 ERα, 5‐HT2A, and 5‐HT2C.

Funder

Academy of Scientific Research and Technology

Publisher

Wiley

Subject

Drug Discovery

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