Exploring metallo-supramolecular architectures: towards recognition of functional nucleic acid structures for fighting disease

Craig, James Samuel ORCID: 0000-0001-6128-9117 (2023). Exploring metallo-supramolecular architectures: towards recognition of functional nucleic acid structures for fighting disease. University of Birmingham. Ph.D.

Craig2023PhD.pdf
Text - Accepted Version
Restricted to Repository staff only until 1 December 2024.
Available under License All rights reserved.
Download (13MB) | Request a copy

Abstract

The work in this thesis investigates the non-canonical DNA binding and in vitro blood stability of modified metallo-supramolecular cylinders, their CB[10] rotaxanes, and metallo-supramolecular pillarplexes. These investigations looked at the rotaxane formed by the metallo-supramolecular cylinder and CB[10], revealing inhibition of their exceptional DNA binding, where their pseudo-rotaxane showed minor change. This set the precedent for unparalleled control of their DNA binding, pushing development of a modified rotaxane system allowing for their controlled biological release. Towards this, a rotaxane of the metallo-supramolecular cylinder was designed with a capping group which cleaved in the presence of glutathione, allowing glutathione dependant release of cylinder and restoration of its unprecedented DNA binding. Due to the functional success of these systems in vitro, in vivo studies have entered an initial planning stage. Towards this, a method for the separation and detection of metallo-supramolecular cylinders and their rotaxanes from rats whole blood was developed, allowing quantitative detection of metal ion concentration and intact structure determination. Finally, we report the first studies into the DNA binding of new metallo-supramolecular pillarplexes. This revealed potent DNA binding and an affinity for DNA 4WJ’s and forks. We also observe a difference in DNA binding which is dependent on the metal in the pillarplex, either gold or silver, suggesting both may have different modes of action in biological systems, and potential for different theragnostic applications.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):