Cytotoxic Hydrogen Bridged Ruthenium Quinaldamide Complexes Showing Induced Cancer Cell Death by Apoptosis

This report presents the first known p-cymene ruthenium quinaldamide complexes which are stablized by a hydrogenbridging atom, [[{(p-cym)RuIIX(N,N)}{H+ }{(N,N)XRuII(p-cym)}][PF6] (N,N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [p-cymRu(-X)2]2 with a functionalised quinaldamide ligand. When filtered over NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H+ , which are counter-balanced by a PF6 counterion. Xray crystallographic analysis is presented for six new structures with O···O distances of 2.430(3)-2.444(17) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4'-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index > 1. Mechanistic studies showed a clear correlation between IC50 values and induction of cell death by apoptosis

Synthesis of novel functionalised β-ketoiminate and β-diketonate metal complexes for their use in anti-cancer treatment

This thesis is concerned with the synthesis, characterisation and evaluation of novel metal complexes for their application as anti-cancer agents. It contains the in vitro cell results, along with a range of other techniques to determine their biological relevance and their potential as anti-cancer agents. Chapter 1 contains an introduction to the project including a literature search, previously synthesised complexes and project aims Chapter 2 presents the synthesis and characterisation of novel β-diketonate and β-ketoiminate ligands. X-ray crystallographic data are analysed for some of the ligands. Chapter 3 discusses the synthesis and characterisation of novel β-ketoiminate ruthenium chloride complexes. X-ray crystallographic data are analysed for all of the complexes. Chapter 4 introduces the MTT technique for assessing cytotoxicity, and presents in vitro activities for the library of complexes synthesised in Chapter 3. Chapter 5 looks at modifications of the previous ruthenium (II) complexes, introducing new ligands and iridum metal centres. X-ray crystallographic data for all of these complexes has been discussed, along with in vitro activity against a range of cell lines. Chapter 6 introduces hypoxia and states the cytotoxicities of a range of complexes under 1.0% and 0.1% oxygen concentrations. Chapter 7 discusses mechanistic studies on the complexes, including hydrolysis, hydrophobicity, Comet assay, apoptosis and thioredoxin reductase inhibition. Chapter 8 introduces the previous group IV work within the group and an extension of the library by synthesis of β-ketoiminate titanium complexes. X-ray crystallographic analysis is discussed where applicable. Chapter 9 contains experimental details and characterisation data for all compounds described in Chapters 2, 3, 5 and 8. Also protocols for all the biological studies. Appendix presents a summary of X-ray crystallographic structure analysis for any crystals obtained within this wor