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

Cytotoxic Hydrogen Bridged Ruthenium Quinaldamide Complexes Showing Induced Cancer Cell Death by Apoptosis

This report presents the first known p-cymene ruthenium quinaldamide complexes which are stablized by a hydrogenbridging atom, [[{(p-cym)RuIIX(N,N)}{H+ }{(N,N)XRuII(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H+ , which are counter-balanced by a PF6 counterion. Xray crystallographic analysis is presented for six new structures with O···O distances of 2.430(3)-2.444(17) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index > 1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis

CCDC 937283: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937282: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937280: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937279: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937278: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937281: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 937277: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures