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, 8g, 8h, and 8f with IC50 values (3.78, 9.25, and 12.11 μM) shown significant anti-proliferative activity against MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. However, the most potent compounds, 8g and 8h of this series, were less effective against MDA-MB-231 (ER- and HER2-) cell line with IC50 value (18.53 and 26.24 μM), respectively. More remarkably, pyrazole-chalcone-piperidine hybrids 8g and 8h exhibited more than 4-fold selectivity for MCF-7 cell line than MDA-MB-231. Further cell cycle analysis and Annexin V/PI investigation on the MCF-7 cell line suggest that compounds were able to stop mitosis at the G2/M phase and thereafter trigger cell death. Western blotting test demonstrated the change in expression of ER-α receptor protein in MCF-7 cell lines. In addition, structural analysis of the docking study indicates that compounds 8g and 8h 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 8g and 8h 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.

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

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