Synthesis and analysis of pseudo-octahedral metal complexes as anticancer agents

Abstract

Chemotherapy is one of the most predominantly used treatments for cancer. Identifying desirable features required of anticancer agents has rapidly developed alongside our growing understanding of the disease. Metal complexes are of interest as drug candidates as they provide advantages over purely organic systems via modular synthesis, variable geometries and oxidation states. Currently, platinum drugs such as cisplatin remain the most common metal-based treatments, despite their known toxicity towards healthy cells. Viable complexes are therefore sought as alternatives that overcome the limitations of platinum drugs.
The synthesis and analysis of three piano-stool metal complex series are described, each investigating a distinct mechanism of action. Firstly, pyridylphosphinate complexes were employed as potential DNA-binding agents. The complexes possess a labile monodentate halide ligand, which exchanges intracellularly, forming the aqua species, enabling the binding of DNA. The metal, arene and ligand substituents were varied to tune the properties of the complexes. Of the resulting systems, few displayed notable cytotoxicity, and these complexes were pursued no further.
The bulk of this thesis focusses on HDAC enzymes as a discrete target for anticancer therapy. New complexes were developed incorporating arene-metal motifs along with ligands designed to trigger HDAC inhibition. The biological properties of this series were explored and revealed moderate to good cytotoxicity, as well as HDAC inhibition to be the likely mechanism of action. Structural modifications of the parent complexes were devised to optimise selectivity between HDAC enzyme isoforms. Relative to the ligand alone, an increase in specificity of the metal-ligand complexes was observed, successfully demonstrating the benefits of incorporating a metal-arene motif. Biological assays including cellular uptake, catalytic domain selectivity and uptake mechanism are reported to examine the varied behaviour of these complexes.
Hypoxic activation was the final mechanism of action studied. Two complexes were synthesised possessing a reducible protecting group, to produce the active species selectively under conditions of hypoxia. Such activity was utilised to minimise off-target binding and enhance tumour region selectivity.