Potent anticancer 5-fluorouracil platinum(IV) prodrugs

Area of Science:

• Medicinal Chemistry
• Nanomedicine
• Cancer Biology

Background:

• Platinum-based chemotherapy remains a cornerstone in cancer treatment, but resistance and toxicity limit efficacy.
• Developing novel platinum(IV) prodrugs offers a strategy to overcome these limitations through improved stability and targeted delivery.
• Incorporating cytotoxic agents like 5-fluorouracil (5FU) into platinum scaffolds can create synergistic anticancer effects.

Purpose of the Study:

• To synthesize and characterize novel platinum(IV) prodrugs functionalized with 5-fluorouracil (5FU) derivatives.
• To evaluate the in vitro cytotoxicity and mechanistic pathways of these platinum(IV) complexes against a panel of cancer cell lines.
• To compare the efficacy of the platinum(IV) prodrugs with existing platinum-based chemotherapeutics like cisplatin.

Main Methods:

• Synthesis and full characterization of six platinum(IV) complexes featuring 5FU-acetate or 5FU-methoxybutanoate ligands.
• In vitro cytotoxicity assays across diverse cancer cell lines to determine half-maximal inhibitory concentrations (GI₅₀).
• Mechanistic studies involving reactive oxygen species (ROS) generation and mitochondrial membrane potential assessment in cancer cells.

Main Results:

• All synthesized platinum(IV) complexes demonstrated significant in vitro cytotoxicity.
• Complex 6, [Pt(IV)(56Me₂Phen)(1S,2S-diaminocyclohexane)(5FU-methoxybutanoate)(OH)](NO₃)₂, exhibited exceptional potency with a GI₅₀ of 1 nM against prostate cancer cells.
• Complex 6 showed up to 1400-fold greater activity than cisplatin and was more potent than its platinum(II) precursor, with 5FU-methoxybutanoate derivatives being more effective than 5FU-acetate analogues.
• Mechanistic studies revealed that complexes 5 and 6 induce oxidative stress and mitochondrial dysfunction in cancer cells.

Conclusions:

• The incorporation of 5FU derivatives into platinum(IV) prodrugs significantly enhances anticancer potency and introduces novel mechanisms of action.
• Platinum(IV) prodrug 6 represents a highly promising candidate for further development in cancer therapy due to its superior efficacy and favorable mechanistic profile.
• These findings support the potential of platinum(IV) prodrugs as a next-generation cancer treatment strategy, offering improved therapeutic outcomes.