Mechanistic Insights into Ascorbate-Mediated Activation of Pt(IV) Prodrugs: Axial-Ligand Modulation of Dissociative Reduction Pathways and Redox Latency
Year: 2026
Type: preprint
Abstract: Pt(IV) coordination compounds act as anticancer prodrugs that are intracellularly reduced to cytotoxic Pt(II) species, a process whose selectivity and kinetics depend critically on the nature of the axial leaving (L L ) and bridging (L B ) ligands. Using DFT/IEFPCM calculations in water, we examined the ascorbate-mediated reduction of six [PtIV(NH 3 ) 2 Cl 2 (L L )(L B )] complexes bearing different axial-ligand combinations of chloride, bromide, and dichloroacetate (DCA): L L /L B = Br/Cl, Cl/Cl, DCA/Cl, as well as DCA/Br, Cl/Br, and Br/Br. For the full series, the mechanistic analysis was therefore focused on the inner-sphere pathway involving nucleophilic attack of the ascorbate enolate at the C β center (M2), characterized as concerted yet highly asynchronous. Both axial ligands modulate the activation barrier, charge-transfer efficiency, and Pt-L bond dissociation, but the bridging ligand exerts the dominant effect: L B = chloride derivatives display the highest free-energy barriers (Δ[Δ ‡ G298] ≈ 2-4 kcal mol -1 ), high charge-transfer percentages (49%-50%) and later transition states relative to L B = bromide analogs. Additionally, the activation barrier is most strongly associated with the extent of charge transfer and its coupling to C β –L B bond formation, rather than the overall bond-structural event. These results suggest that L B primarily determines the dissociative-reduction behavior, while L L provides secondary control, thereby providing a mechanistic framework for understanding how axial-ligand combinations influence redox latency in Pt(IV) scaffolds.
Source: ChemRxiv
Authors: F. Salazar, E. L. Coitiño
Institution: Universidad de la República de Uruguay
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225346069