A New Class of Coumate Benzimidazole Hybrids as BRCA 1 Mimetics Through Unconventional Binding Mode; Synthesis and Preliminary Cytotoxicity Screening

Abstract

It was found that breast cancer susceptibility protein 1 (BRCA 1) binds to estrogen receptor alpha (ERα) and inhibits its activity by direct interaction between domains within the amino terminus of BRCA 1 and the carboxy terminus of ER alpha. The present work focuses to identify a new class of BRCA 1 mimetics that work differently from conventional anti-estrogens. A novel class of hybrids having coumate and benzimidazolone scaffolds were designed to mimic BRCA 1 protein, suppressing the tumor activity of breast cancer cells. In silico molecular docking studies of the designed ligands were performed on BRCA 1 binding cavity of ER alpha. The designed hybrids which gave significant docking scores and had optimum binding interactions with key residues were selected for synthesis and in vitro assay. The compounds NY1 and NY2 exhibited significant effects on suppressing MDAMB- 231 cells in the concentration of 24 μg/ml and 44 μg/ml, respectively.