Ruthenium(II) Polypyridyl Complexes As Potential Anticancer Drugs: Synthesis, Characterization, Cell Permeability And Investigation Of Their Hypoxia-selectivity

Abstract

Research on biological activity of ruthenium polypyridyl complexes (RPCs) continues to attract interest as these complexes have shown promising anti-cancer activity both in vitro and in vivo. The mononuclear RPC, [(phen)₂Ru(tatpp)]²⁺ (MP) and the related dinuclear complex [(phen)₂Ru(tatpp)Ru(phen)₂]⁴⁺ (P) have been shown to both intercalate with DNA and show potentiated DNA cleavage under anaerobic and reducing conditions¹ ² as well as show good selectivity and cytotoxicity towards malignant cell lines in vitro and tumors in vivo. Both complexes contain the redox-active tatpp ligand which is thought to be the essential component for the observed biological activity. This thesis is focused on developing improvements to the stereoselective syntheses of the chiral complexes, ΔΔ-P and Δ-MP, and a new analog [(phen)₂Ru(tadbp)]²⁺ (B) and Δ-B which contains a modified tatpp ligand that is only capable of binding one Ru ion. We hypothesize that the new complex B will retain the promising biological activity of the related MP complex, but will be more lipophilic and less reactive with extraneous metal ions than MP. Moreover this thesis explores the ability of these large complexes to transverse the cell membrane and get into cell and the cell nuclei by isolating treated cells and nuclei and determining their ruthenium content by atomic absorption method. The data show that the two complexes examined ΔΔ-P and Δ-MP, are able to quickly pass into cancer cells (H-358) and are observed to build up in the nuclei, which were postulated due to their high affinity for binding to DNA. Finally, the hypothesis that some of these complexes may be more cytotoxic towards cell under hypoxic stress was examined. HCC-2998 cells treated with ΔΔ-P and Δ-MP under normoxic and hypoxic conditions for a period of 4 hour showed similar responses to the dosing of these drugs. While this is not the definitive study on this hypothesis, it does suggest that there is little to no enhancement of the cytotoxicity of these RPCs due to hypoxia.