Structure–activity optimization of Deferasirox–derived aroyl hydrazones: Synthesis, DFT characterization, and mechanistic insights into selective anticancer activity against colon and breast cancer
Ömer Dilek, Muzaffer Dükel, Fatema Zarzour, Çiğdem Karabacak Atay, Tahir Tilki
Abstract
Dysregulated iron metabolism is increasingly recognized as a hallmark of tumor progression in solid malignancies, including colon and breast cancers. Deferasirox (DFX), an oral Fe(III) chelator, exhibits anticancer activity; however, its structural optimization may enhance potency and selectivity. Here, six novel DFX-based aroyl hydrazone derivatives were synthesized, structurally characterized, and evaluated in vitro. Quantum chemical calculations and two-dimensional NMR confirmed their configurations, while molecular dynamics simulations demonstrated stable protein-ligand interactions. Compound 5e exhibited potent and selective cytotoxicity against triple-negative breast cancer (MDA-MB-231) and metastatic colon cancer (SW620) cells. Mechanistic studies revealed that 5e induces apoptosis and cell cycle arrest in a dose-dependent manner, with reactive oxygen species (ROS) generation playing a central role. Increased oxidative stress triggered autophagy, as evidenced by upregulation of Beclin-1, ATG5, and LC3 conversion. Co-treatment with the ROS scavenger N-acetylcysteine significantly reversed these effects, confirming the ROS-mediated mechanism. These findings highlight compound 5e as a multi-targeted anticancer agent warranting further in vivo and combination therapy investigations.