Diaryl Pyrazole-Chalcone Hybrids as Novel ER-α Modulators: Docking, Synthesis and Anti-Breast Cancer Activity Evaluation

The novel diaryl-pyrazole chalcone hybrids were designed and developed as new selective estrogen receptor modulators (SERMs) for the treatment of breast cancer. Among them, ۸g, ۸h, and ۸f with IC۵۰ values (۳.۷۸, ۹.۲۵, and ۱۲.۱۱ μM) shown significant anti-proliferative activity against MCF-۷ cells compared to the positive control Raloxifene and Tamoxifen. However, the most potent compounds, ۸g and ۸h of this series, were less effective against MDA-MB-۲۳۱ (ER- and HER۲-) cell line with IC۵۰ value (۱۸.۵۳ and ۲۶.۲۴ μM), respectively. More remarkably, pyrazole-chalcone-piperidine hybrids ۸g and ۸h exhibited more than ۴-fold selectivity for MCF-۷ cell line than MDA-MB-۲۳۱. Further cell cycle analysis and Annexin V/PI investigation on the MCF-۷ cell line suggest that compounds were able to stop mitosis at the G۲/M phase and thereafter trigger cell death. Western blotting test demonstrated the change in expression of ER-α receptor protein in MCF-۷ cell lines. In addition, structural analysis of the docking study indicates that compounds ۸g and ۸h bind in an antagonistic conformation that is similar to SERMs through substantial pi-pi stacking, hydrogen bonds, and Van der Waals interactions. All of these findings strongly indicate compounds ۸g and ۸h as a unique class of potent ER antagonists with promising potential for the SERM development for the treatment of BC. From these findings, we concluded that these compounds can be further developed as potential SERM and more quality data needs to be gathered from different models to claim their clinical use. We are aiming to report the same in near future.

Keywords:

breast cancer , Pyrazole , Chalcone , Estrogen Receptor-α , Piperidine Basic Side Chain