Structure-activity optimization of Deferasirox-derived aroyl hydrazones: Synthesis, DFT characterization, and...

Area of Science:

• Oncology
• Medicinal Chemistry
• Biochemistry

Background:

• Dysregulated iron metabolism is a key factor in solid tumor progression.
• Deferasirox (DFX), an iron chelator, has demonstrated anticancer properties.
• Structural optimization of DFX may improve its anticancer potency and selectivity.

Purpose of the Study:

• To synthesize and characterize novel Deferasirox-based aroyl hydrazone derivatives.
• To evaluate the in vitro anticancer activity of these derivatives against breast and colon cancer cells.
• To elucidate the mechanism of action of the most potent derivative.

Main Methods:

• Synthesis and structural characterization of six novel DFX derivatives.
• In vitro cytotoxicity assays using MDA-MB-231 (breast) and SW620 (colon) cancer cell lines.
• Mechanistic studies including apoptosis assays, cell cycle analysis, ROS generation measurement, and autophagy marker evaluation.

Main Results:

• Compound 5e demonstrated potent and selective cytotoxicity against triple-negative breast and metastatic colon cancer cells.
• Compound 5e induced apoptosis and cell cycle arrest in a dose-dependent manner.
• Reactive oxygen species (ROS) generation was identified as a key mediator, triggering autophagy.

Conclusions:

• Compound 5e is a promising multi-targeted anticancer agent with potential for further investigation.
• The ROS-mediated induction of apoptosis and autophagy is the primary mechanism of action.
• Further in vivo studies and combination therapy investigations are warranted for compound 5e.