Design and Synthesis of 3, 5-Diphenylpyrazole derivatives as Selective Estrogen Receptor Modulators

Abstract

This exploratory work encompasses synthetic chemistry to develop novel 3, 5- diphenylethanone derivatives compounds based on the medicinally relevant scaffold of pyrazole as that of standard SERM i.e. Tamoxifen and Raloxifene. Specific strategies for the synthesis of novel analogues were used and were subjected to modeling and docking studies for analyzing the ER subtype selectivity. The in-silico studies were conducted in order to attain a better insight into the interactions of these molecules with their target receptor in order to study their subtype selectivity and preferential binding site. The various orientations taken by ligands while binding the estrogen receptor-α were studied over 1ERR (PDB) using Schrodinger Maestro environments. The anti-cancer potential of these derivatives were evaluated in estrogen receptor-positive cell lines in an in vitro assay, exploring MCF-7 and Zr-75-1 cell lines. Amongst all, the derivatives that displaced promising anticancer activity (4-chloro substituted, compound 4b) were selectively screened for in vivo anti-cancer activity subjected to NMU administration mammary carcinoma in female Sprague- Dawley rat. As hormone estrogen has been largely implemented in the metastasis of breast cancer, it has become imperative to measure levels of the hormone in tumor-affected animals. The percentage of incidences, tumor latency, tumor burden, and tumor volume was measured after sacrificing the experimental animals.