Stereochemical Modulation of Palladacyclopentadienyl Complexes Bearing Diphosphine Ligands: A Key to Enhanced DNA Interaction and Anticancer Activity

Palladacyclopentadienyl complexes represent a uniquely stable and structurally rigid class of organopalladium compounds with significant potential for anticancer drug development. Here, we report the first systematic exploration of palladacyclopentadienyl complexes supported by a diverse set of achiral and chiral diphosphine ligands, including DPPF, DPPE, DPPP, DPPBz, DPEPhos, Xantphos, BINAP, and Chiraphos. All complexes were obtained in high yields and fully characterized, confirming bidentate coordination and preservation of the rigid palladacyclopentadienyl framework. Biological evaluation against cisplatin‐sensitive, cisplatin‐resistant, and high‐grade serous ovarian cancer cell lines revealed that complexes bearing DPPF and DPPBz exhibit sub‐micromolar cytotoxicity combined with marked selectivity for cancer cells over non‐tumoral fibroblasts, outperforming cisplatin and carboplatin. Notably, pronounced differences in activity were observed between enantiomeric BINAP‐ and Chiraphos‐based complexes, representing a rare example of strong chirality‐dependent cytotoxicity in metal‐based agents. Molecular docking analyses were used to rationalize the observed trends, correlating cytotoxicity with the number and nature of predicted non‐covalent interactions formed with DNA. These results highlight palladacyclopentadienyl–diphosphine complexes as a highly tunable platform for anticancer drug design and identify DPPF‐ and DPPBz‐based derivatives as promising lead compounds for further preclinical evaluation.