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Title: Organo-iridium anticancer and antibacterial complexes
Author: Millett, Adam J.
ISNI:       0000 0004 5371 1578
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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This thesis is concerned with the design of half-sandwich iridium(III) complexes of the type [(η5-Cp*)Ir(2-(Rˈ-phenyl)pyridine-R)X]0/+ (Cp* = pentamethylcyclopentadienyl), X = Cl- or pyridine derivatives) as anticancer agents, with particular focus on the effects that functionality in the chelating and monodentate ligands has on their chemical and biological properties. A set of phenyliminopyridyl (ImPy) complexes of the type [(η5-Cpx)Ir(ImPy)Cl]PF6 (Cpx = Cp*, tetramethyl(phenyl)-cyclopentadienyl (CpxPh) or tetramethyl(biphenyl)- cyclopentadienyl (CpxBiPh) was also synthesised and their solution chemistry and potential applications as antibacterial and anticancer agents investigated. Electron donating (-CH3, -OH, -CH2OH and –OCH3) or electron withdrawing (-F, -CF3 -CHO and –NO2) groups were introduced to various positions on the 2-PhPy ligand, giving rise to seventeen complexes [(η5-Cp*)Ir(2-(Rˈ- phenyl)pyridine-R)Cl]. Three X-ray crystal structures were determined, showing the expected pseudo-octahedral configuration. The functional groups have a profound effect on the resulting anticancer activities against a range of cell lines. Some complexes showed activity against A2780 human ovarian cancer cells comparable to cisplatin, and similar activity to [(η5-CpxPh)Ir(2-phenyl)pyridine)Cl]. The complexes all show similar extents of hydrolysis. The complexes preferentially bind to the model nucleobase 9-EtG over 9-MeA, and show the ability to catalytically oxidise the coenzyme NADH to NAD+. Contrasting anticancer activities were found for structural isomers. The hydrophobicity is related to substituent type and position on the ligand. The more hydrophobic complexes accumulated in A2780 cells to a greater extent. The extent of accumulation appeared to correlate with the potency of the complexes. The most potent complex [(η5-Cp*)Ir(2-(2ˈ-methylphenyl)pyridine)Cl] 13 (IC50 = 1.18 μM against A2780 cells) was modified via replacement of the chlorido monodentate ligand with pyridine derivatives (18 = pyridine (Py), 19 = 4- dimethylaminopyridine (Py-NMe2), 20 = 4-trifluoromethylpyridine (Py-CF3). The X-ray crystal structure was determined for 19. These pyridine complexes show less monodentate ligand release in aqueous solution and less binding to 9-EtG than parent complex 13. Complexes 13 and 19 show mild catalytic activity towards the oxidation of NADH to NAD+. Reactivity towards glutathione (GSH) decreased only in the case of 19 when compared with the parent complex 13. The reaction products include [(η5-Cp*)Ir(2-(2ˈ-methylphenyl)pyridine)(S-O)G] (sulfenate) and [(η5- Cp*)Ir(2-(2ˈ-methylphenyl)pyridine)(S-O2)G] (sulfinate) which are reliant on the presence of O2. The antiproliferative activity against A2780 cells increased upon enhancement of stability at the monodentate site (19 > 18 > 20 ~ 13) when activity was measured with no cell recovery time, with 19 exhibiting nanomolar activity (IC50 = 650 nM). All of the complexes induced high levels of total reactive oxygen species (ROS). Apoptotic cell death after 24 h recovery time was only observed for the pyridyl complexes. The ability to functionalise 2-PhPy complexes via Schiff base formation was examined using the aldehyde-containing complex [(η5-Cp*)Ir(2-phenyl-5- pyridinecarboxaldehyde)Cl] 6, and new conjugates were synthesised by conjugation to primary amines. Reactions with lysine-containing peptides were analysed by ultrahigh resolution mass spectrometry (UHR-MS) techniques which showed formation of new iridium-peptide conjugates via Schiff base formation with the free amino group of lysine. The imine bond in a complex bearing the fluorescent dansyl moiety (for fluorescence microscopy) was reduced using the hydride source Et3SiH, which appears to involve the metal centre through proposed formation of an Ir-H species. Eighteen [(η5-Cpx)Ir(ImPy)Cl]PF6 complexes with various ImPy ligands were synthesised and characterised, and six X-ray crystal structures were reported. They were found to exhibit more complex aqueous chemistry than the 2-PhPy complexes, but exhibit minimal hydrolysis at biologically-relevant concentrations of chloride, remaining predominantly as the chlorido species. The hydrophobicity of the complexes increased upon extension of the Cpx capping ligand: CpxBiPh > CpxPh > Cp*. The complexes show minimal activity against Gram-negative E. coli but CpxBiPh complexes show good activity (MIC = 8 – 15 μM) against Gram-positive S. aureus bacteria. The antibacterial activity is generally dependent on the hydrophobicity and extension of the Cpx capping ligand. Disruption of the bacterial cell membrane appears to be involved in the mechanism of action. The antiproliferative activity against A2780 cells follows the trend CpxBiPh > CpxPh > Cp*, where the complex [(η5-CpBiPh)Ir(ImPy-NMe2)Cl]PF6 31 exhibits an IC50 value against A2780 cells of 640 nM.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)