Palladium(II) anticancer agents: the intricate case of the Pd-spermine complex

Palladium-based anticancer drugs are promising alternatives to platinum agents, with potential to overcome acquired resistance and reduce side effects. Among them, the dinuclear Pd(II)-spermine complex (Pd₂Spm) has shown notable cytostatic activity in vitro. However, its synthesis mechanism and structural properties remain poorly understood, which hinders further development. This study reports an optimised synthetic route for Pd₂Spm, revealing pH dependence and temperature-induced isomeric changes. These variations were thoroughly characterised by vibrational spectroscopy, leading to the identification of the pure diastereomer (R,S), the enantiomeric mixture ((R,R) and (S,S)) and the mixture containing these three isomers. Cell viability tests were carried out in the human triple negative breast cancer MDA-MB-231 cell line for the diastereomer and the enantiomers and diastereomer mixture, demonstrating equivalent results for these entities (IC₅₀ equal to 2.7 and 2.6 μM at 72 h, respectively). This is the first report of an optimised synthesis and anticancer in vitro assays for a well-defined Pd₂Spm structure. The present findings strengthen the potential of Pd₂Spm as a next-generation anticancer metallodrug, paving the way for preclinical trials.