The development of transition metal complexes to target hypoxic cells

Hypoxic regions (areas of subnormal oxygen levels) are a common feature with solid tumours that have reached a size of 2-3 mm in diameter. Such regions have characteristically responded poorly to conventional anti-cancer treatments such as radiation or chemotherapeutics. It has been previously demonstrated that the specific targeting of these cells is possible with compounds of specific properties, such as tirapazamine.
This thesis describes an exploration of using transition metal complexes of cobalt(III) and copper(II) as hypoxia-selective prodrugs for use in cancer chemotherapy. The aim has been to use both the lowered pH and lowered oxygen levels found within hypoxic regions to activate prodrugs into their cytotoxic active form. Through doing this, the coordination chemistry of medicinally active N-oxide ligands has been expanded upon, including the first transition metal complexes of tirapazamine and the development of a novel series of heteroleptic complexes featuring an N-oxide and 2,2’-dipyridylamine ligand. The solution properties of the prepared complexes and their uncoordinated ligands have been studied so that their behaviour in biological systems can be better understood. The cobalt(III) heteroleptic complexes are shown to have promise for the purpose of improving delivery of N-oxide based drugs, improving their solubility and altering their delivery and release. The complex of a tirapazamine analogue [Co(tpz-CN)(dpHa)2]2+ was shown to release the cytotoxic N-oxide rapidly under hypoxic conditions, but promisingly, this dissociation appears to be hindered in the presence of oxygen. In vitro cytotoxicity studies on this complex showed it to have the same IC50 value as its N-oxide ligand, providing promise for the heteroleptic system as prodrugs.