Copper(II) N,N,O-Chelating Complexes as Potential Anticancer Agents.

Quim Peña,Giuseppe Sciortino,Pau Bayón,A Jalila Simaan,Julia Lorenzo,Mercè Capdevila,Òscar Palacios,Sylvain Bertaina,Olga Iranzo,Jean-Didier Maréchal

doi:10.1021/acs.inorgchem.0c02932

Abstract

Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (−H, −Cl, and −Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in the dimeric form in the solid state and adopt the same conformation. The mass spectrometry and electron paramagnetic resonance results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (dimethyl sulfoxide and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblast cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 μM in HeLa cells, which is in the range of cisplatin and improved with respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds.

Highlights

Metals and their inorganic complexes show an enormous versatility in front of strictly organic compounds for the development of therapeutic agents
In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblasts cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 μM in HeLa cells, which is in the range of cisplatin and improved respect to carboplatin), placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds
The results indicate that C1 is able to partially trigger apoptosis in HeLa cancer cells, where at least about 12% of cells are in the early apoptotic stage (Table S6)

Summary

INTRODUCTION

Metals and their inorganic complexes show an enormous versatility in front of strictly organic compounds for the development of therapeutic agents. The possibility of having several oxidation states, different coordination numbers and diverse geometries gives rise to a broader spectrum of tuneable properties.[1] Among them, Cu complexes have become promising alternatives for cancer treatment during the two last decades.[2,3,4,5] Copper is a physiological metal, being widely present in many biomolecules and playing a remarkable role in a diversity of biochemical processes due to its interesting Cu(II)/Cu(I) redox pair.[6] one of the main potentialities of Cu as antiproliferative agent lays on its capability to form reactive oxygen species (ROS) inside the cells The generation of these entities (H2O2, O2.-, HO·, etc.) is reported to damage DNA, and to offer a putative discrimination between healthy and non-healthy cells.[7,8] The lack of selectivity in cancer therapy has always been a downside in this field, giving rise to severe sideeffects.[9] Tumours contain a more reducing environment respect to healthy tissues. Speciation and the putative active species in solution are discussed hereby from a theoretical approach, and the mechanism of action is thorough evaluated and related to the redox behaviour of the Cu(II) complexes

RESULTS AND DISCUSSIONS

B BIOLOGICAL

CONCLUSIONS