Chemotherapeutic Potential of Fluorouracil‐Platinum (IV) Prodrugs Against Cisplatin‐Resistant Colorectal Cancer Cells

ABSTRACT Fluorouracil‐platinum(IV) prodrugs represent a novel class of multimechanistic chemotherapeutics with enhanced anticancer potential. The prodrugs Pt IV P‐5FUMeOBut and Pt IV 56‐5FUMeOBut were actualized by derivatising the clinical drug 5‐fluorouracil (5FU) and coordinating it to platinum(IV) complexes, leveraging the established cytotoxicity of their platinum(II) precursors, Pt II PHEN SS and Pt II 56ME SS . The rationale behind this design is to combine the DNA synthesis‐disrupting antimetabolite activity of 5FU with platinum‐based cytotoxicity, aiming to enhance therapeutic efficacy. This study evaluates the in vitro potency of Pt IV P‐5FUMeOBut and Pt IV 56‐5FUMeOBut in colorectal cancer models, assessing their cellular uptake, cytotoxicity, and effects in 3D spheroid cultures. Comparative analyses with cisplatin and 5FU explore their impact on cell survival, reactive oxygen species production, mitochondrial membrane potential, and cell‐cycle progression. Mechanistic insights are further examined through apoptosis and necrosis assays, proteomic profiling, and western blot analysis of key signalling pathways. These findings contribute to the preclinical development of fluorouracil‐platinum(IV) prodrugs as potential candidates for cancer therapy.