Palladium(II)-Diphosphine/Lapachol complexes: Structural Insights and Selective Activity against Cisplatin-Resistant Ovarian Cancer

Abstract Here, we have developed and structurally characterized a series of palladium(II) complexes combining diphosphine ligands and the natural product lapachol (lap), namely [Pd(dppp)(lap)]PF6 (1), [Pd(dppb)(lap)]PF6 (2), and [Pd(dppf)(lap)]PF6 (3), where dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1′-bis(diphenylphosphino)ferrocene, to explore structure–activity relationships in anticancer systems. The complexes [Pd(dppp)(lap)]PF6 (1), [Pd(dppb)(lap)]PF6 (2), and [Pd(dppf)(lap)]PF6 (3) were synthesized and structurally characterized. X-ray diffraction confirmed O,O-chelation of lap and square-planar geometry around the Pd(II) center. Biological evaluation revealed that the activity of the complexes strongly depended on the diphosphine ligand. The ferrocenyl-containing complex 3 displayed remarkable cytotoxicity and selectivity toward ovarian cancer cells, particularly toward the cisplatin-resistant A2780cis line, outperforming cisplatin. Mechanistic studies demonstrated that complex 3 induced apoptosis in a concentration-dependent manner, as evidenced by morphological changes, inhibited colony formation, and cell cycle arrest in the sub-G1 phase, while activity in 3D tumor spheroid models was retained. On the basis of these results, complex 3 was effective under physiologically relevant conditions. DNA-binding experiments suggested that complexes 1–3 interacted with DNA weakly via groove binding rather than classical covalent mechanisms. Moderate to strong binding of the complexes to human serum albumin supported that they can potentially be transported in biological media. Overall, these findings highlight the critical role played by the diphosphine ligand in modulating the biological activity of the complexes and identify complex 3 as a promising candidate for developing new metallodrugs to target resistant tumors via mechanisms that differ from the mechanisms of platinum-based agents.