Antitumor effects of a tetradentate amido-carboxylate ligands and corresponding square-planar palladium(II) complexes toward some cancer cells. Crystal structure, DFT modeling and ligand to DNA probe docking simulation.

Novel square-planar palladium(II) complexes with O-N-N-O-type ligands H4mda (H4mda=malamido-N,N'-diacetic acid) and H4obp (H4obp=oxamido-N,N'-di-3-propionic acid) were prepared and characterized. The ligands coordinate to the palladium(II) ion via two pairs of deprotonated ligating atoms with square chelation. A four coordinate, square-planar geometry was verified crystallographicaly for the K2[Pd(mda)]·H2O complex. The binary and ternary systems of Pd(II) ion with H4mda or H4obp (L) as primary ligands and guanosine (A) as secondary ligand were studied in aqueous solutions in 0.1 M NaCl ionic medium at 25 °C by potentiometric titrations. In addition, calculations based on density functional methods (DFT) were carried out. A natural bonding orbital analysis indicated that the Pd-N bonds are three-centric in nature and mainly governed by charge transfer via a strong delocalization of the oxygen lone pair with "p" character into the bonding Pd-N orbital. Mononuclear palladium(II) complexes together with amido acid N,O-containing ligands were tested against several tumor cells and reveal significant antitumor activity and lower resistance of tumor cells in vitro than cisplatin. In this paper, interactions of palladium complexes with DNA are discussed in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems. Docking simulation on DNA dodecamer or 29-mer (Lippard solved crystal structures), suggests several favorable interactions with the hydrogen pocket/binding site for the incoming ligands. These results support amidoacids/Pd complexes as novel antitumor drugs and suggest that their potent cell life inhibition may contribute to its anti-cancer efficacy.