Co(III) Complexes as Pro-drugs for Cancer Therapy

Cancer is the leading cause of death in Canada and is characterized by irregular and uncontrolled cell growth. In many cases this uncontrolled cell growth results in a solid mass of cells called a tumor. When the inner part of a tumor is sequestered from blood vessels, the nutrient and oxygen levels decrease. The term “hypoxia” is used to describe low oxygen level in tissue. Hypoxia induces more reducing conditions in a tumor in comparison to normal tissue. The objective of this project was to generate a series of octahedral Co(III) complexes for the treatment of cancer. We designed pro-drugs that are initially administered to the body in an inactive form, and can be selectively activated under the hypoxic (reducing) conditions in tumors. In this work, a series of octahedral Co(III) salen complexes were synthesized incorporating 1-methylimidazole in axial positions. We investigated the stability of the complexes in solution, and the effect of different para-ring substituents on the Co(III) / Co(II) reduction potential. We concluded that the reduction potentials of the complexes were correlated with the electron donating ability of the para-ring substituents, and that a geometry change from octahedral to square-planar upon reduction leads to axial ligand release. Building on these results, coumarin fluorophores were then attached to the Co(III) complexes via a functionalized imidazole. We found that the fluorescence of the coumarin was largely quenched while bound to the Co(III) center. Ligand release was then studied in the presence of excess competing ligands and in the presence of a reducing agent. Our results suggest that both ligand exchange and reduction play a role in axial ligand release in these systems.