Ruthenium and Osmium Bis-Arene Complexes with Biologically-Active Ligands

Abstract

The inclusion of biologically-active ligands into organometallic complexes offers much scope for the design of novel drugs with enhanced, targeted activity. Studies on such complexes indicate that new mechanisms of action are possible when combining the bioactivity of the ligand with the properties inherent to the metal, leading to the possibility of overcoming current drug resistance pathways. This thesis is concerned with the synthesis and characterisation of ruthenium(II) and osmium(II) bis-arene complexes containing biologically-active ligands and their potential application as anticancer agents. Four groups of ligands are investigated: indole derivatives, aspartame, tamoxifen and flavonoids. Both indole derivatives studied resulted in the formation of complexes which were unstable, due to either polymerisation of the ligand or decomposition of the complex as a result of loss of the bound ligand with time. X-ray structural data obtained for [(eta6-p-cymene)Ru(eta6-1-methylindole-3-acetic acid)](PF6)2 revealed that the latter may be a result of partial loss of eta6-coordination due to tilting of the indole ring away from the metal. Much more stable complexes were generated with aspartame, however the effect of the metal on the structure, electronics, acidity and decomposition of the ligand all resulted in the complexes being incapable of binding to and activating the human sweet taste receptor. Antiproliferative studies found that ruthenium and osmium complexes of tamoxifen were not active against hormone-dependent mcf-7 breast cancer cells although they were able to mimic the isolated ligand under certain conditions. Here, the inactivity is most likely a result of the organometallic fragment being too bulky to fit into the receptor active site. Although no cytotoxic activity was observed, evidence of intercalation of the complexes into DNA was obtained. Dual anticancer activity was discovered for two ruthenium complexes of flavonoids: [(eta6-p-cymene)Ru(eta6-flavanone)](PF6)2 and [(eta6-biphenyl)Ru(eta6-flavanone)](PF6)2. Although the complexes are very similar in structure, the first displayed moderate cytotoxic activity against both A2780 and A549 cancer cells (IC50 30 – 40 microns), which may be a result of an observed DNA interaction, while the second was selectively highly cytotoxic towards A549 cancer cells (IC50 ~ 6 microns) and showed no evidence of targeting DNA. Moreover, antioxidant properties inherent to the ligands were found to be enhanced on metal binding, giving the complexes additional potential in applications for the prevention of cancer. Significantly, this work has identified the first anticancer active metal bis-arene complexes of biologically-active ligands, therefore demonstrating the validity of such an approach to the design of novel drugs.