Ferrocene-embedded flavonoids targeting the Achilles heel of multidrug-resistant cancer cells through collateral...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Drug Discovery

Background:

• Multidrug resistance (MDR) in cancer is a major challenge, often mediated by transporters like MRP1.
• Collateral sensitivity offers a strategy to target cancer cells overexpressing drug efflux pumps.

Purpose of the Study:

• To design and synthesize novel ferrocene-containing compounds (chalcones, aurones, flavones) as potential anticancer agents.
• To investigate their efficacy against drug-resistant cancer cells overexpressing MRP1.
• To explore the concept of collateral sensitivity for selective cancer therapy.

Main Methods:

• Synthesis of 14 ferrocene-embedded chalcone, aurone, and flavone derivatives.
• Evaluation of compounds for their ability to induce glutathione (GSH) efflux in MRP1-overexpressing tumor cells.
• Cytotoxicity assays on both sensitive and resistant cancer cell lines.

Main Results:

• At least one compound from each structural series effectively induced GSH efflux at 5 and 20 μM.
• Two flavone derivatives demonstrated superior cytotoxicity against resistant cancer cells compared to sensitive ones.
• A selectivity ratio greater than 9.1 was achieved for the most potent flavone compounds.

Conclusions:

• Ferrocene-containing chalcones, aurones, and flavones show promise as anticancer agents.
• The developed compounds effectively induce GSH efflux and exhibit selective cytotoxicity against MRP1-overexpressing resistant cancer cells.
• These findings provide a foundation for further optimization of these compounds for targeted cancer therapy.