Optimising photopharmacology for future clinical applications
| dc.contributor.advisor | Abell, Andrew | |
| dc.contributor.advisor | McLaughlin, Robert | |
| dc.contributor.author | Palasis, Kathryn Angela | |
| dc.contributor.school | School of Physics, Chemistry and Earth Sciences : Chemistry | |
| dc.date.issued | 2024 | |
| dc.description.abstract | The research undertaken in this thesis is focused on addressing some of the key challenges associated with the field of photopharmacology, in order to help progress it toward a clinical application. The concept of a “magic bullet” for treatment of diseases is explored in Chapter 1, and photopharmacology is presented as a promising approach to the development of more selective drugs. The physical and chemical properties of the photoswitches azobenzene and spiropyran are discussed in detail, and the major challenges involved in developing photopharmaceuticals are identified. Two of the most significant challenges are explored by the work in this thesis; (1) maximising the difference in biological activity between isomeric states, and (2) delivering light deep inside the body for local activation of a photoswitchable drug. Chapter 2 investigates the effect of 3D structure of a photoswitchable drug on its ability to modulate biological affinity toward a target. Here, two different classes of photoswitchable drugs – small molecule and peptide-based – are designed and synthesised as inhibitors of the same protease: trypsin. The best small molecule inhibitor showed a 3.4-fold difference in biological activity between isomers, while the best peptidic inhibitor showed a difference of >5-fold. Molecular modelling and docking show this is likely due to a large change in the structural positioning of key binding residues in the peptides upon isomerisation, which is not as prominent in the small molecules. Therefore, this is an important consideration in the design of new photopharmaceuticals with a maximised difference in activity between isomers. Chapter 3 is focused on optimising the photostationary state in spiropyran derivatives upon irradiation, to aid development of more efficient photoswitches and hence improved photopharmaceuticals. Derivatives of the common spiropyran 6-nitro BIPS were synthesised, with functional groups of various electron donating/withdrawing character substituted at the 5-indoline position. Following UV irradiation, 1H NMR was used to determine the degree of ring opening for each analogue, switching from the spiropyran isomer to the protonated merocyanine isomer. The electronic effects of the substituent were found to correlate with the degree of ring opening, such that the compound with the most electron donating group at the 5-indoline position showed the greatest proportion of protonated merocyanine in the irradiated sample. These results can help to inform the development of photopharmaceuticals based on spiropyran, with an optimised photostationary state in the ring opened direction. Chapter 4 explores one of the most significant challenges facing the clinical progress of photopharmacology – delivering light efficiently, and safely, deep inside the body for local activation of photoswitchable drugs. Here, an optical fibre is presented as a potential tool to address this issue. Light delivered by an optical fibre is shown to activate an anticancer photoswitchable drug, which is characterised by its dose-response against colon cancer cell line HCT-116. The two-fold difference in activity between isomeric states demonstrates optical fibres are a feasible tool for light delivery to activate a photoswitchable anticancer drug, and hence could be used in a clinical setting for photoswitchable chemotherapy. | |
| dc.description.dissertation | Thesis (Ph.D.) -- University of Adelaide, School of Physics, Chemistry and Earth Sciences : Chemistry, 2025 | en |
| dc.identifier.uri | https://hdl.handle.net/2440/144846 | |
| dc.language.iso | en | |
| dc.provenance | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals | en |
| dc.subject | photochemistry | |
| dc.subject | photoswitches | |
| dc.subject | photopharmacology | |
| dc.subject | azobenzene | |
| dc.subject | spiropyran | |
| dc.subject | biophotonics | |
| dc.subject | enzymes | |
| dc.subject | optical fibres | |
| dc.title | Optimising photopharmacology for future clinical applications | |
| dc.type | Thesis | en |
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