George Hughes
Design and Mechanism of Action of Novel Organoiridium(III) Azopyridine Anticancer Complexes.
Supervisors: Prof. Peter Sadler (Department of Chemistry, Professor) and Prof. Lawrence Young (Warwick Medical School, Pro-Vice-Chancellor)
My PhD project involved the synthesis and characterisation of novel and optimised Ir(III) complexes to expand the range of treatable cancers by exploiting the redox modulation that these complexes can achieve in cancer cells as well as other possible mechanisms of action. The cytotoxicity of the novel Ir(III) complexes was investigated in a variey of cancer cell lines as well as healthy human cells.
In this time I travelled to Grenoble, France to work at the ESRF synchrotron as well as Guangzhou and Beijing, China as part of a collaboration with SYSU Cancer Center in Guangzhou testing my drugs against a variety of their cell lines.
During this trip I attended the ICBIC International Conference in Beijing, presented a poster and gave a talk to an audience of ~500 describing my work.
Publications:
Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action. George M. Hughes*, Jessica M. Hearn*, Isolda Romero-Canelón, Alison F. Munro, Belén Rubio-Ruiz, Zhe Liu, Neil O. Carragher and Peter J. Sadler. Metallomics 2018, 10, 93-107. DOI:10.1039/C7MT00242D
http://pubs.rsc.org/en/content/articlelanding/2017/mt/c7mt00242d#!divAbstract
Design and Mechanism of Action of Novel Organoiridium(III) Azopyridine Anticancer Complexes.
The final version of my thesis was submitted on the 3rd March 2018, after a successful viva. I then spent 7 months backpacking around New Zealand.
Thesis 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 [CpXIr(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 effects 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.
2013 - 2014: MSc, Mathematical Biology and Biophysical Chemistry (Merit), University of Warwick
Modules Included:
- Cellular systems and biomolecules
- Mathematical Models of Biological Systems
- Introduction to chemical aspects of biological systems
- Techniques for the characterisation of biomolecules
- Microscopy and Imaging
- Numerical methods for Modelling
- Molecular modelling
- Quantitative biology
- Statistics for Data Analysis
- Warwick Interdisciplinary Science Transferable Skills
Plus three 8-week miniprojects:
- Biophysical Miniproject - Acetolactate decarboxylase (ALDC) selective active-site binder synthesis. (Project consisted of synthetic organic chemistry, analytical chemistry and X-ray crystallography) Supervisor: Prof. Martin Wills & Prof. Vilmos Fulop.
- Theoretical Miniproject - Analysis of TCR sequencing data. (Project consisted of programming in C++ and statistical analysis of large datasets in R) Supervisor: Dr. Sascha Ott & Dr. Nigel Dyer.
- Experimental Miniproject - Medicinal chemistry of syncytial virus inhibitors. (Project consisted of cell biology, virology and computational chemistry for drug screening in silico) Supervisors: Prof. Andrew Easton, Dr. Andrew marsh and Dr. Philip Gould.
2010 - 2013: BSc (Hons), Biochemistry (Upper second-class), University of Warwick
Molecular Biology, Organic Chemistry, Physical Chemistry, Biophysical Chemistry
Biological Spectroscopy, Biostatistics, Advanced Immunology, Oncology and Post-Genomic research.
Completed Labs in Structural Biology, Microbiology, Post Genomic Research, Bioenergetics.
Undertook a final year project in Immunology involving particle gun mediated cell transformation and confocal microscopy.
