Antiproliferative Activity and Structure-Activity Relationships of Novel Au(III)-Thiosemicarbazone Complexes: An Evaluation of the PPP4 Series

The development of metal-based anticancer agents has expanded beyond platinum drugs such as cisplatin, which primarily target DNA through covalent binding following intracellular aquation. While effective, Cisplatin is limited by severe toxicities like nephrotoxicity and neurotoxicity and the emergence of multidrug resistance (MDR). In contrast, thiosemicarbazones have shown to exert cytotoxicity through a “double-punch” mechanism involving intracellular iron sequestration and the generation of cytotoxic reactive oxygen species (ROS). This paper evaluates the antiproliferative capability of two sixth-generation thiosemicarbazone ligands, (E)-3-phenyl-1-(pyridine-2-yl)prop-2-en-1-one-morpholine-1-thiosemicarbazone (PPP4MT) and the pyrrolidine-substituted analogue, (E)-3-phenyl-1-(pyridine-2-yl)prop-2-en-1-one-pyrrolidine-1-thiosemicarbazone (PPP4PyrT), together with the corresponding Au(III) complexes [Au(PPP4MT)Cl]⁺ and [Au(PPP4PyrT)Cl]⁺. Au(III) was incorporated because it is a d8 metal centre that typically adopts square-planar geometry (analogous to Pt(II)), potentially providing greater complex stability while retaining thiosemicarbazone-driven biological targeting. The compounds were assessed against the iron-dependent MDA-MB-231 Triple-Negative Breast Cancer (TNBC) cell using a 72h MTT cellular viability assay, with data collected using their half-maximal inhibitory concentrations, IC50 values. The results showed that free ligand PPP4MT was the most potent agent. While coordination to Au(III) resulted in chemically stable square-planar complexes, leading to a reduction in antiproliferative potency for both ligands compared to free ligands. Physicochemical properties may contribute to differences in potency (e.g., permeability/solubility), but they do not fully explain the observed activity, indicating mechanistic factors also play a key role. Analysis also revealed that Au(III) coordination increased molecular weight and lipophilicity, which may reduce alignment with common drug-likeness guides. These findings demonstrate Au(III) modifies structure-activity relationships in the PPP4HAT ligand series, which therefore warrants further mechanistic validation using assays which directly measure intracellular metal handling and oxidation species.