Palladium( <scp>ii</scp> ) 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 <i>in vitro</i>. 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 (<i>R</i>,<i>S</i>), the enantiomeric mixture ((<i>R</i>,<i>R</i>) and (<i>S</i>,<i>S</i>)) 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 <i>in vitro</i> 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.