Design and synthesis of new metallo-organic complexes and their evaluation as anti-cancer agents. Synthesis, characterisation and biological evaluation of novel, late first row transition metal schiff base complexes, as anti-cancer metallopharmaceuticals

Abstract

This work is concerned with the design and synthesis of the cheap, late first row transition metal complexes of Schiff base ligand systems. The prepared complexes readily afford systematic variation in order to probe potency and understand the role of metal, chelating ligands and anionic ligands when carrying out their cytotoxic effect. This study has lead to a better understanding of the action of these classes of complex and will be used to direct the design of new anti-cancer metallopharmaceuticals going forward. This thesis details the synthesis of a library of Schiff base macroacyclic ligands and their novel late first row transition metal complexes with varying anionic counterparts. The creation of a library with several degrees of variability provides a wide array of parameters to afford subtle variation in structure and chemistry e.g. denticity, co-ordination mode, chelate hole size, metal centred redox potentials, hydrolysis rates, co-ordinative saturation, lipophilicity, solubility and more. Complexation of the ligands was carried out by the free ligand and a novel macroacyclic metal template approach using the cheap late first row transition metal salts of Cobalt (II), Nickel (II), Copper (II) and Zinc (II) plus one Ru (III) complex. Structural studies of the 80 generated complexes was carried out by vibrational spectroscopy, elemental analysis, mass spectrometry, magnetic susceptibility and NMR. Single crystal X-ray structures have been determined with 20 reported in this thesis. All ligands act as tridentate ligands in all except one case to form monomeric distorted trigonal-bipyramidal, square-pyramidal or octahedral structures. In the case of zinc nitrate, the ligand L2PhMe acts as a tetradentate ligand to give a distorted octahedral structure. Paramagnetic NMR and solution magnetic susceptibility of paramagnetic complexes was achieved by the Evans NMR method and analysis of the solution NMR showed that L2R and L3R ligands display 2-fold symmetry and are likely either tetradentate in solution or a fast exchange between imine N-donar sites is occurring even down to -65°C. The majority of the resulting complexes of L1R were screened against a panel of three cancer cell lines. Several categories of complex were able to afford structure activity relationships. It was discovered that the ligand is indeed essential for activity of the metal salts against the panel of cell lines and it was largely discovered that the variation in ¿tail group¿ and anionic coordinating ligands played little role in providing a dramatic variation in activity of the metal salt. In general all L1R complexes displayed moderate cytotoxicity showing a trend in activity with respect to the metal in the order RuIII¿CoII>CuII¿ZnII>NiII, over a 6 day exposure to the three cell panel RuIII was shown to be the most potent metal of the L1R series providing IC50 values of 4.6 (0.7) and 7.5 (1.2) ¿M against the DLD-1 and H460 cell lines respectively, which is Ca. 4.6 and 15 iii times less potent than cisplatin to the same cell panel respectively. RuIII was also discovered to be the only metal to provide an IC50 value from a 1 hour exposure to the DLD-1 cell panel. The value of 20.4 (3.5) ¿M is a moderate figure but again Ca. 10 fold less potent than cisplatin for the same test. The L2R and L3R complexes could not be screened by the same comprehension due to their low solubilities. However the lone screen that was possible from the very sparingly soluble complex [CuCl2(L3Bui)] gave the most exciting result and most potent complex of this thesis. After a 6 day exposure, [CuCl2(L3Bui)] gave IC50 values of 4.3 (0.1) and 2.9 (0.1) ¿M against the DLD-1 and H460 cell lines respectively. These values are merely 4 and 6 fold more than Cisplatin to the same cell lines respectively and demonstrates the potential of this class of complex as cytostatic agents. Further studies utilising a semi-quantitative DNA damaging assay, demonstrated that all first row complexes can damage DNA when in the presence of hydrogen peroxide, with the exception of ZnII complexes. CoII appeared to afford the greatest DNA damage with the most intsense bands for double strand breaks and the CuII complex of the ligand L3Bui also demonstrated a greater DNA damage as opposed to its L1Bui analogue.