Platinum(II) and Copper(II) complexes of asymmetric halogen-substituted [NN'O] ligands: Synthesis, characterization, structural investigations and antiproliferative activity

Abstract

In order to better understand the effect of structure, halogen substitution, metal ions and ligand flexibility on antiproliferative activity, eight Cu(II) complexes and eight Pt(II) complexes were obtained of 2,4-X₁,X₂-6-((pyridine-2-ylmethylamino)methyl)phenol and 2,4-X₁,X₂-6-((pyridine-2-ylmethylamino)ethyl)phenol (where X is Cl, Br, or I) ligands. The compounds were characterized with various techniques, such as FT-IR, NMR, elemental analysis and single-crystal X-ray diffraction (SCXRD). The X-ray structures showed that ligand acts as a bidentate and tridentate donor in Cu(II) and Pt(II) complexes, respectively. This difference in structures is due to the use or non-use of base in the preparation of complexes. Also, complexation of Cl₂-H₂L₁ with CuCl₂·2H₂O gives two different types of structures: polymer (Cl₂-H₂L₁-Cu^polymer) and dimer (Cl₂-H₂L₁-Cu^dimer), according to the crystal color. In addition, ¹H NMR spectrum for platinum complexes display two set of signals that can be attributed to the presence of two isomers in solution. All complexes induced moderate to high reduction in A2780 and HCT116 cancer cell viability. However, only complexes bearing iodo- substituted in ligands exhibited significantly low cytotoxicity in normal fibroblasts when compared with cancer cell lines. The antiproliferative effect exhibited by I₂-H₂L₂-Cu complex in A2780 cell line was due to induction of cell death mechanisms, namely by apoptosis and autophagy. I₂-H₂L₂-Cu complex does not cause DNA cleavage but a slight delay in cell cycle was observed for the first 24 h of exposition. High cytotoxicity was related with the induction of intracellular ROS. This increase in intracellular ROS was not accompanied by destabilization of the mitochondrial membrane which is an indication that ROS are being triggered externally by I₂-H₂L₂-Cu complex and in agreement with an extrinsic apoptosis activation. I₂-H₂L₂-Cu complex has a pro-angiogenic effect, increasing the vascularization of the CAM in chicken embryos. This is also a very important characteristic in cancer treatment since the increased vascularization in tumors might facilitate the delivery of therapeutic drugs. Taken together, these results support the potential therapeutic of the I₂-H₂L₂-Cu complex.

Keywords: Antiproliferative activity; Copper(II) complexes; Crystal structures; Halogen-substituted ligands; Platinum(II) complexes.