Pt(IV) Complexes Incorporating CDC25A/NF-κB Dual Inhibitory 1,4-Naphthoquinone Derivatives Trigger Multimodal Cell...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Cancer chemotherapy faces challenges with drug resistance and targeting specific proteins.
• CDC25A is a key regulator of cell cycle progression and a challenging therapeutic target.
• Platinum(IV) prodrugs offer potential for improved efficacy and reduced toxicity in cancer treatment.

Purpose of the Study:

• To synthesize and characterize novel platinum(IV) complexes with dual CDC25A/NF-κB inhibitory ligands.
• To evaluate the in vitro and in vivo anticancer activities of these novel platinum(IV) complexes.
• To elucidate the underlying mechanisms of action for the most potent platinum(IV) candidate.

Main Methods:

• Synthesis and characterization of platinum(IV) complexes (Pt5-Pt13) incorporating 1,4-naphthoquinone derivatives.
• In vitro cytotoxicity assays and mechanistic studies in A2780 cancer cells.
• In vivo efficacy and toxicity evaluation in A2780 xenograft mouse models.

Main Results:

• Novel platinum(IV) complexes (Pt5-Pt13) were successfully synthesized and characterized.
• Pt6, featuring ligand c2, demonstrated potent inhibition of CDC25A and NF-κB.
• Pt6 induced cancer cell death via DNA damage, cell cycle arrest, apoptosis, and ferroptosis, showing superior tumor inhibition in vivo compared to cisplatin.

Conclusions:

• Pt6 represents a promising platinum(IV) prodrug for cancer chemotherapy, effectively targeting CDC25A.
• The multimodal mechanism of action of Pt6 contributes to its significant anticancer efficacy and low toxicity.
• This strategy offers a novel approach to overcome CDC25A "undruggability" in cancer treatment.