Design, synthesis and characterization of novel paracetamol derivatives to target breast cancer

1257-1272Most breast cancers are Estrogen Receptor-positive type. In the mammary epithelial, estrogen controls many cellular activities such as proliferation, differentiation and migration. There are two genetically distinct and functional estrogen receptors (ERs), ERα and ERβ, belonging to the superfamily of nuclear receptors for steroid/thyroid harmones. Estrogenexert its functions in different tissues by binding with its receptors, including alpha and beta (ERα and ERβ). Estrogen Receptor alpha (ERα) controls breast tissue development and progression of breast cancer. Paracetamol is one of the most widely used medicines. A recent experimental study suggests that paracetamol may have several pharmacological effects other than its well known analgesic/antipyretic properties. The docking study was performed on different paracetamol derivatives using Schrodinger 2015 (maestro 10.1) on Human Estrogen Receptor Alpha Ligand-Binding Domain (1XP6) and Endothelial nitric oxide synthase (3NLE). The in silico studies indicate that N-(4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl) acetamide derivatives exhibit comparable docking score and good hydrogen bond interactions at Ligand binding domain of ERα and 3NLE. Based on the docking studies, a new series of N-(4-((1H-1,2,3-triazol-4-yl)methoxy)phenyl) acetamide derivatives have been synthesized by employing click chemistry approach. Nine compounds have been evaluated for their cytotoxicity in MCF-7 cell line and anti oxidant activity. Many of the synthesized compounds exhibit potent cytotoxic and anti oxidant activity. In particular 5c, 5g, and 5b compounds show most potent cytotoxicity with IC50 value of 19.83, 20.57, 20.83 µg/mL respectively and 5e and 5f show most potent anti oxidant activity with IC50 value of 0.4, 0.5 µg/mL respectively