Ruthenium Polypyridyl Complexes for Biological Applications in Imaging and as Anti-Cancer Agents

Abstract

Ruthenium-polypyridyl complexes containing extended aromatic ring systems exhibit attractive photophysical properties and have been shown to bind strongly to DNA. Such properties make complexes like these suitable for a broad range of biological applications. This thesis, entitled ?Ruthenium Polypyridyl Complexes for Biological Applications in Imaging and as Anti-Cancer Agents?, is focusing on DNA binding and treatment of cancer and aims to develop novel Ru(II) polypyridyl complexes, which can be used as luminescence dyes for imaging or as photodynamic therapeutic (PDT) agents in cancer treatments. Chapter 1 gives a basic introduction to the background of the problem treated in the thesis by, firstly, providing an overview of DNA and its structure and a brief description of the various binding modes, by which molecular species can interact with DNA. Following this overview, relevant Ru(II) polypyridyl complexes are described, including their application as DNA binding, cellular imaging, or anti-cancer agents. A critical literature review of multivalent binding is given to help with a conceptual understanding. New, more accurate methods to calculate binding parameters are also introduced. This chapter then concludes by outlining recent examples of similar Ru(II) polypyridyl complexes and other biologically relevant molecules developed in the Gunnlaugsson group. In Chapter 2, synthesis, characterisation and photophysical properties of two Ru(II) polypyridyl complexes are explored with a new, extended aromatic moiety as one of the ligands. The photophysical properties of the compounds show promising features for use in imaging by being emissive in aqueous and/or organic solvents. The DNA binding properties of the two new Ru(II) complexes are investigated. Their binding interactions with DNA are evaluated using various spectroscopic techniques and both complexes are seen to bind strongly to DNA through intercalation. The potential use as imaging probes of one of the complexes is demonstrated by a dramatic enhancement of the emission by the compound in aqueous environment upon binding to DNA. In Chapter 3 the synthesis and characterisation of compounds based on 1,10-phenanthroline-5,6-dione are described. In Chapter 4 the activity at the cellular level for these and the two new DNA binding complexes is evaluated. The behaviour of the complexes in HeLa cervical cancer cells has been studied, their cytotoxicity has been described, and their ability to act as luminescent dyes and PDT agents has been explored. One of the two new complexes showed great potential for use in PDT with a large increase in toxicity at photoactivation. Further, Ru(II) complexes with naphthalimide based Tr?ger?s bases as bridging ligands are evaluated for use in PDT. The naphthalimide based Tr?ger?s bases that are tested do not show potential for use in PDT, however some of them show anti-cancer activity or potential for use in cellular imaging. Chapter 5 describes the investigation into the site specific and cooperative binding of the two enantiomers of a novel ruthenium polypyridyl complex. This includes studies of the binding to oligomeric and polymeric DNA. Both enantiomers show strong selectivity, with preferential binding to AT-rich DNA. Investigations of the delta enantiomer show positive cooperativity for binding to natural DNA. In Chapter 6 the possibility of functionalising gold nanoparticles with ruthenium-polypyridyl complexes has been explored, an approach that may, among other things, help in cellular uptake. The aims of this project are the development of new Ru(II) polypyridyl complexes that can conjugate to the surface of gold for application as biological imaging agents and cancer therapeutics due to their high Ru(II) complex loading and rapid cellular uptake. Finally, Chapter 7 outlines the experimental procedures, and presents the synthesis and characterisation of the compounds discussed within this thesis. Following this, literature references and Appendices are provided, the latter containing supplementary experimental data to support the work described in the main text.