Design, synthesis, in silico, and biological evaluation of novel pyrazolopyrimidinone-based estrogen receptor...

A series of pyrazolo pyrimidinone derivatives was designed and evaluated as estrogen inhibitors.

The newly synthesized compounds were tested for their antiproliferative activity on 60 NCI cell lines.

Compound 5a emerged as the most potent antiproliferative agent, with a mean growth inhibition percentage (GI%) of 111.5%, followed by compounds 5b, c, d. The NCI selected compounds 5a and 5b for five-dose assay, yielding GI50 values of 2.57-17.7 µM and 11.1-24.1 µM, respectively. Furthermore, flowcytometry analysis of the cell cycle on the MCF-7 cell line revealed that compounds 5a-d induced cell cycle arrest at the G1 phase. Moreover, western blot was done for compounds 5a and 5b, showed two-fold greater potency than tamoxifen at 10 µM. The cytotoxicity of compounds 5a-d was evaluated against a normal human skin fibroblast cell line (HSF), which exhibited favorable safety profiles. A molecular docking study was conducted to investigate the binding mode and affinity of the new compounds to the estrogen alpha receptor (ERα). Finally, molecular dynamics simulations of compounds 5a and 5b were performed to support the stability of the protein-ligand complexes.

Compounds 5a and 5b showed remarkable activity toward tumors which have higher estrogen expression.