Design, synthesis of novel quinazolinone-based oxobutanonitrile derivatives as antiproliferative agents targeting human breast cancer
Background: Breast cancer (BC) is among the leading causes of death among women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications. Objective: Novel quinazolinone-based oxobutanonitrile derivatives were designed, synthesized, and screened for in vitro anti-BC 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 in 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-BC 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.