Heteroleptic copper (II) chemotherapeutic agents.

Abstract

In this study, a range of heteroleptic copper(II) chelates were synthesized as chemotherapeutic agents. Two primary heteroleptic copper(II) chelates, [Cu(L)(H2O)2]NO3 and [Cu(L1)(H2O)2]NO3 were successfully synthesized and characterized. These complexes had Schiff base ligands HL and HL1 coordinated, both with an N,N’,O donor atom set which were synthesized by the reaction of 2-aminophenol with 2-pyridinecarbaldehyde for HL and the condensation of salicylaldehyde with 8-aminoquinoline for HL1. Both Schiff base ligands were synthesized via the eco-friendly solid state technique. The reaction between (CuNO3)2 and Schiff base HL yielded [Cu(L)(H2O)2]NO3 which was further reacted with three co-ligands: 1,10-phenantroline (phen), 1,10-phenantroline-5-amine (phen-NH2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz) to afford three secondary heteroleptic copper(II) chelates. The secondary heteroleptic copper(II) complexes have been synthesized using a mechanochemical technique that is eco-friendly, efficient, simple and afforded excellent yields. The co-ligand dppz was prepared from the reaction of 1,10-phenanthroline-5,6-dione with o-phenylenediamine. The complex [Cu(phen-NH2)2Cl]Cl was synthesized by reacting CuCl2 with 1,10-phenantroline-5-amine. The ligands have been characterised by mass spectrometry (MS), IR and NMR spectroscopy, while the chelates have been characterised by EPR, MS, elemental analysis as well as UV/vis spectroscopy. The solid state structures of three heteroleptic complexes were elucidated using single crystal X-ray diffraction. X-ray crystallography showed that [Cu(L)(H2O)2]NO3 and [Cu(L1)(H2O)2]NO3 complexes had square pyramidal geometries with various combinations of N and O-donor ligands. The solution state coordination geometry of copper(II) complexes [Cu(L)(H2O)2]NO3, [Cu(L)(phen)]NO3, [Cu(L)(phen-NH2)]NO3 and [Cu(L)(dppz)]NO3 were found to be trigonal bipyramidal using EPR spectroscopy. The DNA binding affinities of the chelates were measured using fluorescence competitive binding assays. The binding affinities range from 2.79 × 105 M-1 for [Cu(L)(H2O)2]NO3 to 5.31 × 106 M-1 for [Cu(phen-NH2)2(Cl)]Cl. The order of all complexes in terms of increasing binding strength is: [Cu(L)(H2O)2]NO3 < [Cu(L)(phen)]NO3 < [Cu(L)(dppz)]NO3 < [Cu(L)(phen-NH2)]NO3 < [Cu(phen-NH2)2(Cl)]Cl. The five copper(II) chelates synthesized were screened against a panel of four human cell lines. These cell lines are: HEK293 (healthy embryonic kidney cells) which was used as a control, MDA-MB (triple negative cancer cells), HELA (cervical cancer cells) as well as SHSY5Y (human neuroblastoma cells). From the cell screening, the EC50 values were calculated. The complex [Cu(L)(dppz)]NO3 had the lowest EC50 values while [Cu(L)(H2O)2]NO3 had the highest EC50 values. The results showed that four complexes are highly cytotoxic towards tumour cells, more so than the well-known chemothepeutic agent cisplatin. The complex [Cu(L)(H2O)2]NO3 showed lower cytotoxicity, however, it has greater selectivity towards tumour cells. The cytotoxicity of the compounds varies with different cells; hence each has a unique cytotoxicity profile and could be used for a specific type of cancer. There is little correlation between the binding affinities of complexes and their cytotoxicity, this suggest that the mechanism of action could include the production of ROS in vitro, which are known to cleave the DNA and induce apoptosis. Significantly, all the complexes synthesized in this work showed lower toxicity towards the healthy cell line than the tumour cell lines. It was also shown that the combination of the Schiff base ligand and co-ligand was an important factor in the cytotoxicity. The redox activity of copper and the production of reactive oxygen species (ROS) are likely key in the cytotoxicity of the complexes.