Modulating the antitumoral activity by the design of new platinum(II) compounds: Synthesis, characterization, DFT, ultrastructure and mechanistic studies.

The synthesis, physico-chemical characterization, Density functional theory (DFT) calculation and cytotoxicity against five human tumoral cell lines (THP-1, U937, Molt-4, Colo205 and H460) of four new platinum(II) coordination compounds are reported, i.e. [Pt(HL1)Cl]·H2O (1), [Pt(HL2)Cl]·H2O (2), [Pt(HL3)Cl]·H2O (3) and [Pt(HL4)Cl]·H2O (4). The ligands contain N2O donor sets. Furthermore, H2L3 and H2L4 present α and β-naphthyl groups respectively, which are absent in HL1 and H2L2. X-ray diffraction studies were performed for complex (3), indicating the formation of a mononuclear platinum(II) complex. Complexes (3) and (4), which contain α and β-naphthyl groups respectively, have presented lower IC50 (inhibitory concentration) values than those exhibited by complexes (1) and (2). The mechanism of cell death promoted by complexes (3) and (4) was investigated, suggesting that, toward U937 cell line, the α isomer promotes death by apoptosis and the β isomer by necrosis. Transmission and scanning electron microscopy investigations are in agreement with the loss of mitochondrial membrane potential (ΔΨm) observed by JC-1 mitochondrial potential sensor and indicate that the activity of complex (3) against U937 cell line is mediated by an apoptotic mechanism associated with mitochondrial dysfunction. A quantification of caspases 3, 6, 8 and 9 indicated that both the intrinsic and extrinsic pathways are involved in the apoptotic stimuli. Based on DFT calculations all the Pt(II) complexes present the same coordination environment for the metal centre, indicating that the higher cytotoxic activities exhibited by complexes (3) and (4) are related to the presence of the α and β-naphthyl groups in the ligand structure.