Potent anticancer 5-fluorouracil platinum(IV) prodrugs

Six platinum(IV) prodrugs incorporating 5-fluorouracil (5FU) derivatives in the axial positions were synthesised, purified, fully characterised, and their biological activity assessed. The 5FU derivatives, 5FU-acetate and 5FU-methoxybutanoate, were successfully coordinated to [Pt(P L )(1 S ,2 S -diaminocyclohexane)(OH)₂] 2+ scaffolds, where P L = 1,10-phenanthroline (Phen) or 5,6-dimethyl-1,10-phenanthroline (56Me₂Phen). All complexes exhibited exceptional in vitro cytotoxicity across a broad panel of cancer cell lines, with [Pt IV (56Me 2 Phen)(1 S ,2 S -diaminocyclohexane)(5FU-methoxybutanoate)(OH)](NO 3 ) 2 ( 6 ) demonstrating the lowest GI₅₀ of 1 nM against the prostate Du145 cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 6 being up to 1400-fold more active in selected cancer cell lines. Complexes incorporating the 5FU-methoxybutanoate ligand ( 5 and 6 ) were notably more cytotoxic and lipophilic than their 5FU-acetate analogues ( 1 – 3 ), with 6 also exhibiting ~2-fold greater potency than its platinum(II) precursor. Further studies in the HT29 colon cancer cell line revealed that 5 and 6 induced sustained elevations in reactive oxygen species (ROS) and substantial reductions in mitochondrial membrane potential, indicating that oxidative stress and mitochondrial dysfunction contributed to their cytotoxicity. Collectively, these findings demonstrate that the incorporation of 5FU into platinum(IV) prodrugs enhances both potency and mechanistic activity, with prodrug 6 emerging as a highly promising anticancer candidate. Platinum(IV) prodrugs comprising of 5-fluorouracil derivatives in the axial position exhibit nanomolar GI 50 cytotoxicity, increased ROS production and decreased mitochondrial membrane potential, with 5-fluorouracil being released after reduction. • Novel platinum(IV) prodrugs synthesised, characterised and biologically evaluated • Exceptional in vitro cytotoxicity as low as 1 nM across cancer cell lines • Lead prodrug 6 is up to 1400-fold more cytotoxic than cisplatin • Prodrugs 5 and 6 induce ROS and mitochondrial dysfunction