Needham, Russell J. (2016) Organo-osmium anticancer complexes with novel azo-ligands. PhD thesis, University of Warwick.

Preview

PDF WRAP_Theses_Needham_2016.pdf - Submitted Version - Requires a PDF viewer. Download (178Mb) | Preview

Request Changes to record.

Abstract

Piano-stool iodido Os(II) arene complexes containing AZPY (phenylazopyridine) π-acceptor bidentate ligands have been previously shown to exhibit potent anticancer activity and mechanisms of action that involve ROS generation, and differ greatly from early Os(II) arene complexes baring σ-donor bidentate ligands. The aim of this thesis was to explore Os(II) complexes containing other types of azo-ligands as well as continue our studies into AZPY complexes. Develop methods for improving the solubility of complexes, explore their
intracellular activation, and further understand the mechanisms in which ROS levels are elevated inside cells.

Firstly I explored Os(II) arene complexes with AZBTZ (phenylazobenzothiazole) bidentate liagnds. It was found that AZBTZ ligands can undergo unaided cyclometallation with Os(II) to form N,C-coordinated osmacycles as well as N,N-coordination. The amount of cyclo-metallation taking place seemed to be dependent on steric factors and occurred more for iodido complexes than chlorido and bromido analogues. The osmacycles were more stable than N,N-coordinated species and exhibited unique properties such as regio-specific deuteration of the aniline ring, but were too hydrophobic for biological evaluation.

A total of 31 new Os(II) arene AZPY complexes were synthesised using the previously determined structure-activity relationships as a basis. The majority contained alkoxy and glycolic side chain substituents on the AZPY ligand, which was achieved via a novel synthesis protocol. Their trends in anti-cancer activity, solubility, lipophilicity and cell uptake were explored. It was found that varying the anion was the best method for improving aqueous solubility without affecting activity, lipophilicity or uptake. Key complexes were found to be very active against OE19 oesophageal cancer cells, were capable of inducing apoptosis and elevating ROS levels in A2780 cells, as well as causing cell cycle arrest in different phases of the cell cycle.

Complexes [Os(ɳ6-p-cym)(5-EtO-AZPY)I]+ and [Os(ɳ6-p-cym)(AZPY-NMe2)I]+ were labelled with radioisotope 131I (β-/γ emitter, t½ 8.02 d) in Kings College London. They were relatively stable in human blood serum and cell culture medium over 24 h. However, in the presence of MCF-7 cells, rapid dissociation of the iodide monodentate ligand was observed in the supernatants. Cell uptake studies revealed a spike in 131I uptake after 5-10 min, which proceeds to steadily decline. The complexes seemed to undergo intracellular activation involving dissociation of the iodide ligand, and uptake of the complex is in competition with a rapid rate of iodide efflux, probably involving chloride transport channels.

The aqua species, [Os(ɳ6-p-cym)(5-EtO-AZPY)H2O]2+, was synthesised and its pKa was determined as 4.55, meaning it exists predominantly as a +1 charged hydroxido species under physiological conditions. Using UV-Vis spectroscopy and EPR (DEPMPO spin trap), [Os(ɳ6-p-cym)(5-EtO-AZPY)OH]+, and its chlorido and iodido analogues were found to catabolise H2O2, generating HO· radicals in the process that were capable of cleaving lysozyme protein with effectiveness in the order OH>Cl>I. Interestingly it was discovered that iodide complexes are activated by iodide ligand dissociation in the presence of low concentrations of GSH (75 μM) to form the more active hydroxido species. However, in higher concentrations (7.5 mM), they formed Os-SG and Os-SOG adducts. Likewise, [Os(ɳ6-p-cym)(5-EtO-AZPY)OH]+ and its iodido analogue were both capable of oxidising NADH to NAD+ with effectiveness in the order OH>I. NADH was also capable of activating iodido species in a similar manner and generating the hydroxido species was required for NADH oxidation to proceed.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Antineoplastic agents, Cancer -- Treatment -- Research, Osmium -- Therapeutic use, Organoosmium compounds, Organometallic chemistry
Official Date:	July 2016
Dates:	Date Event July 2016 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J.
Format of File:	pdf
Extent:	x, 346 leaves
Language:	eng

Request changes or add full text files to a record

Repository staff actions (login required)

View Item

Downloads