ABSTRACT
BACKGROUND: Breast cancer (BC) is among the leading causes of death in women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications. OBJECTIVE: Novel quinazolinone-based oxobutanenitrile derivatives were designed, synthesized, and screened for in vitro anti-breast cancer activity. METHODS: The antiproliferative activities were determined using MTT assay against MCF-7 and MDA-MB-231 cell lines. EGFR, ARO, and caspase-9 enzymes were selected to explore the mechanism of action of the most potent compounds. RESULTS: Tested compounds showed better EGFRIs than ARIs. In addition, significant overexpression of caspase-9 level in treated MCF-7 breast cell line samples was observed with the most active compounds. The thienyl derivative 5 induced the greatest activation in caspase-9 level in treated MCF-7 breast cancer samples. The o-tolylhydrazone 3b, exhibiting promising ARO inhibition and weak EGFR inhibition, produced a noticeable high overexpression of caspase- 9 and showed pre-G1 apoptosis and cell cycle arrest at G2/M phase for MCF-7 cells and at S-phase for MDA-MB- 231 cells. Docking results revealed that 3b elicited binding affinities to ARO comparable to those of letrozole. CONCLUSION: The obtained results support the therapeutic importance of some of these compounds as anti-breast cancer agents in light of the simple methodology used for their synthesis. Their design offered a way for the optimization and development of apoptotic quinazolinone-based ARO and EGFR inhibitors.
