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Download StatisticsCampbell, Callum Donald James (2020). Functionalisation of DNA binding metallosupramolecular helicate cylinders. University of Birmingham. Ph.D.
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Campbell2020PhD.pdf
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Abstract
Previous work in the Hannon group has shown that metallosupramolecular helicate “cylinders” can bind at the heart of DNA three-way junctions. As pseudo three-way junctions are formed during DNA replication within cells, these cylinders could potentially hinder the uncontrolled cell replication that is associated with cancers, offering them potential as a cancer therapeutic. However, a number of factors have prevented the cylinders from reaching the clinic, including uncertainty around the fate of the compound within cells and the stability of these compounds in solution. These cylinders do not have any feature that
would make them target cancerous cells over healthy cells, a common hurdle in the design of anti-cancer drugs. The work described in this thesis aims to structurally modify triple stranded cylinders to incorporate useful functionalities that could address these hurdles, such as a fluorescent tag to allow tracking of the cylinder in vivo or a receptor targeting moiety that would favour uptake by cancer cells. The work presented is focused on two main aims. The first was to develop a synthetic route to modify the cylinder structure in such a way that the ligands are connected through a covalent “cap”, with the goal of improving upon the physiochemical properties exhibited by previous functionalised cylinders. Various strategies were trialled that used different covalent linkages to connect the cylinder ligands to a capping moiety. A reliable route to a novel tripyridyl-aldehyde cap was developed, yet conditions to synthesise a discrete capped cylinder were not identified. A substantial grounding for further work towards the synthesis of a capped cylinder is set, with recommendations made on what steps should be taken next. The second aim was to synthesis azide functionalised cylinders which could undergo post-assembly modifications with alkynes. Two novel cylinders, Fe2LA3Cl4 and Fe2LB3Cl4, were synthesised. Circular and linear dichroism experiments were performed to investigate the binding behaviour of these cylinders to double stranded DNA, and polyacrylamide gel electrophoresis experiments were performed to investigate their binding to a DNA three-way junction. These investigations show that the additional azide functionalities do not dramatically detract from the desirable DNA binding properties exhibited by the original cylinder. An initial study suggests that one of the novel cylinders undergoes a post assembly modification with a strained cyclooctyne without losing the ability to bind to a DNA three-way junction. This tantalising result justifies further investigation into the potential for these novel azide cylinders to undergo post-assembly modifications.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges > College of Engineering & Physical Sciences | |||||||||
| School or Department: | School of Chemistry | |||||||||
| Funders: | Other | |||||||||
| Other Funders: | School of Chemistry Scholarship | |||||||||
| Subjects: | Q Science > QD Chemistry | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/10452 |
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