Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752499
Title: Design and mechanism of action of novel organoiridium(iii) azopyridine anticancer complexes
Author: Hughes, George Marc
ISNI:       0000 0004 7425 6295
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2018
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Abstract:
This thesis is concerned with the synthesis, characterisation, and purification of 19 organoiridium(III) complexes, seventeen of which are novel. The complexes are of the general structure [CpX Ir(azopyridine)Z]A, where the iridium centre is coordinated to either a pentamethyl-cyclopentadienyl (Cp*) ligand, a tetramethyl(phenyl)-cyclopentadienyl Cpxph ligand, or a tetramethyl(biphenyl)-cyclopentadienyl Cpxbiph ligand. The azopyridine acts as an N,N-chelated bidentate ligand with a variety of substituents, the chemical and biological e↵ects of which are investigated. Z represents a monodentate halido ligand. In this work, complexes with chlorido and iodido ligands in this position are investigated. A represents the counterion to the cationic organoiridium complex. In this work, complexes bearing the hexafluorophosphate (PF6 ), Cl , and I anions are investigated. X-ray crystal structures of eight of the complexes are determined, confirming that the complexes adopt the expected ’piano-stool’ configuration. The anticancer properties of these complexes are thoroughly investigated in multiple cancer cell lines, revealing that several are more potent than many clinically-utilised chemotherapeutics including cisplatin (CDDP), as well as many previously reported metal-based anticancer complexes. The mechanism of action (MoA) of this family of complexes has been investigated, revealing an MoA based on the generation of reactive oxygen species (ROS) and superoxide (SO) in addition to mitochondrial membrane depolarisation. Drugs with this MoA hold the potential to selectively kill cancer cells over normal ones as cancer cells have higher levels of basal ROS and are therefore more sensitive to perturbation of their ROS balance. The charge, solubility, hydrophobicity, hydrolytic behaviour, and mechanism of action (MoA) of these complexes can all be modified with small synthetically trivial adjustments, resulting in highly potent complexes. This demonstrates this family of complexes as an effective and versatile platform for drug design.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.752499  DOI: Not available
Keywords: QD Chemistry ; RC0254 Neoplasms. Tumors. Oncology (including Cancer) ; RM Therapeutics. Pharmacology
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