Cobalt picolinamide complexes as potential anti-cancer agents

This thesis details the synthesis of cobalt picolinamide complexes with potential chemotherapeutic applications. The anti-cancer, anti-bacterial and anti-fungal activity of these complexes was probed, with lead complexes undergoing further mechanistic investigations. Three series of cobalt picolinamide complex were investigated: cobalt(III) trispicolinamide, cobalt(II) bis-picolinamide and cobalt(III) mixed ligand complexes. Cobalt tris-picolinamide complexes consist of a cobalt(III) ion surrounded by three picolinamide ligands, bound through the pyridyl and amide nitrogen atoms. A minor isomer with different ligand coordination was formed under certain reaction conditions, provided that an electron donating group is present as a substituent on the picolinamide ligand. The formation of cobalt bis-picolinamide complexes was also only successful when electron donating groups were present on the picolinamide ligand. These complexes contain a cobalt(II) ion with two picolinamide ligands and two axial thiocyanate ligands. The cis/trans orientation of the thiocyanate ligands varies dependent upon the position of the picolinamide ligand substituent. Mixed ligand complexes consist of a cobalt(III) ion with two picolinamide ligands and one β-diketonate or ferrocenyl β-diketonate ligand. Complexes were screened for their anti-cancer potential against a number of cell lines. Cobalt bis-picolinamide and mixed ligand complexes were non-toxic. Some cobalt tris-picolinamide complexes displayed cytotoxicity, with the minor isomer displaying greater activity than the analogous major isomer. The two lead complexes were active against cancer cells and cancer stem cells. The mechanism of action is proposed to be inhibition of cell proliferation through interruption of the cell cycle at M phase. The lead complexes did not undergo hydrolysis, in contrast to the mixed ligand complexes containing the ferrocenyl β-diketonate ligand. The lead complexes could also adsorb onto an artificial biomembrane surface, unlike the inactive complexes, implying a correlation between cytotoxicity and cellular uptake. Additionally, cobalt bis-picolinamide complexes displayed antifungal activity against C. albicans, with the thiocyanate ligands essential for activity.