Design and Synthesis of Novel Quinazolinone-Based Oxobutanenitrile Derivatives as Antiproliferative Agents Targeting Human Breast Cancer.

Abstract

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. Novel quinazolinone-based oxobutanenitrile derivatives were designed, synthesized, and screened for in vitro anti-breast cancer activity. 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. 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. 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.