Heterometallic palladium(II) complexes as multi-targeting anticancer agents: Synthesis and investigation of the putative mechanism of action.

The development of heterometallic complexes has emerged as a promising strategy in anticancer research due to their ability to act on multiple biological targets simultaneously. In this study, we report a novel synthetic approach to bi- and heterometallic palladium(II) complexes as potential anticancer agents. The reaction of [M(phen)(OOCtBu)2] (M = Zn, Cu, Pd) with the complex [Pd(phen)(MeCN)2](Otf)2 yielded three new water-soluble compounds: heteronuclear complex [PdZn(phen)2(μ-OOCtBu)2(H2O)](Otf)2 (PdZn), the first example of a heterometallic acetamidate-pivalate bridged complex [PdCu(phen)2(μ-OOCtBu)(μ-NHCOMe)(H2O)](Otf)2 (PdCu) and the homometallic complex [Pd2(phen)2(μ-OOCtBu)(μ-NHCOMe)](Otf)2 (PdPd). All complexes were fully characterized by single-crystal X-ray diffraction, IR, UV-vis spectroscopy, and mass spectrometry). The in vitro antiproliferative activity of the complexes was evaluated against HCT116 (colon), A549 (lung), and SKBR3 (breast) cancer cell lines, as well as normal human dermal fibroblasts (HDF). The complexes exhibited submicromolar IC50 values, significantly outperforming cisplatin. Notably, the complex PdPd demonstrated exceptional selectivity towards A549 lung cancer cells (SI = 29.3). DNA binding studies indicated a dual interaction mode involving both intercalation and minor groove binding. Molecular docking simulations suggest that the dissociated [Pd(phen)(NHCOMe)]+ fragment of PdPd act as a plausible pharmacophore, capable of binding to both DNA and the mutant KRAS protein, which is prevalent in A549 cells. The introduction of the heterometal into the complex leads to increased cytotoxicity toward HCT116 and healthy cells, suggesting an additional target of the heterometal fragment - in particular, ROS generation by PdCu. This study highlights the potential of designing palladium complexes that target multiple cellular pathways for enhanced anticancer efficacy.