Elucidating the High Affinity Copper(II) Complexation by the Iron Chelator Deferasirox Provides Therapeutic and...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Deferasirox (Def) is an oral iron chelator investigated for anticancer properties due to cancer cells' high iron demand.
• Concerns exist regarding Def's potential off-target health effects.
• Copper (Cu(II)) binding by Def is explored as a possible off-target interaction.

Purpose of the Study:

• To investigate the aqueous solution stability and speciation of the ternary complex formed between Cu(II), Def, and pyridine.
• To assess the interaction of Def with copper transporters ceruloplasmin and albumin.
• To evaluate the cytotoxicity of the Cu(Def)(pyridine) complex and its protein adducts.

Main Methods:

• UV-Vis and EPR spectroscopy
• ESI-mass spectrometry
• Cyclic voltammetry
• In vitro cytotoxicity assays

Main Results:

• A stable, redox-active, mononuclear Cu(II) complex with square planar geometry was formed.
• Def does not inhibit ceruloplasmin but forms a ternary complex with albumin at the ATCUN site.
• The Cu(Def)(py) complex showed potent, nonselective cytotoxicity against lung cancer and non-cancer cells.

Conclusions:

• Cu(II) complexation by Def may contribute to its toxicity.
• Synergistic cytotoxicity between copper and Def suggests potential for novel drug design.
• Understanding metal-chelator interactions is crucial for developing safer and more effective therapeutics.