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Light-controlled probes for chemical biology

Offenbartl-Stiegert, Daniel; (2020) Light-controlled probes for chemical biology. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Controlling the biological activity of chemical probes with light is of interest in many different areas. In research, it allows to selectively probe or perturb biological systems to understand them better. In biomedicine, photocontrol can improve a drug’s activity towards diseased cells. Light is an ideal trigger as it can be focused spatially and temporally. Furthermore, light is non-invasive and non-toxic. The first aim of this thesis was to synthesise new photo-responsive groups which enable the controlled release of small molecules. These light-responsive groups, also termed photocages, are covalently linked to a target molecule to inhibit its activity. Upon application of light, the photocage is excited and released, so that the activity of the target molecule is restored. Existing photocages absorb at wavelengths at around or below 400 nm. However, to apply photocages in biomedicine the wavelength of absorption must be increased in order to achieve sufficient penetration of tissue and create optically orthogonal photocages. This project aimed to overcome this issue and develop a novel coumarin-based photocage that absorbs at longer wavelengths. The spectroscopic and photorelease properties of the new compound were also investigated. In addition, the electronically excited states of the compound were analysed to attain insight into the mechanism of photorelease. This will allow for improved rational design in the future. The photocage could be used for controlled drug release or to study physiological pathways. The second aim was to build a DNA-based membrane channel with a light-controllable molecular valve based on duplex formation and dissociation. This will allow to control when cargo is transported across the channel. Membrane channels are molecular gate keepers that control trans-membrane transport in physiological systems. Recreating and tuning channels is scientifically exciting since it permits to expand the principle into synthetic biology. Rationally designed channels have predictable properties, enabling their use in biomedicine. Naturally occurring membrane channels are usually composed of polypeptides. However, it is challenging to design and build channels with a predictable structure from intricately folded polypeptides. By contrast, DNA as a building material facilitates a simple rational design. To achieve light-control, several light-switchable azobenzene groups were installed in the lid of the molecular valve to tunably alter duplex formation. The artificial channel could be used for controlled drug release or be incorporated into nanoreactors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Light-controlled probes for chemical biology
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Some third party copyright material has been removed from this e-thesis.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10098251
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