Exploring G-quadruplex topology with photoswitchable small molecules

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


G-quadruplexes (G4) are non-canonical DNA structures that can form from guanine rich sequences. They have been implicated in a variety of biological functions including genome instability, and the inhibition of transcription or translation processes. Targeting G4s by stabilising the secondary structure with small molecule ligands has been proposed as an alternative therapeutic strategy towards various diseases caused by cancers, viruses and bacteria, etc.

However, examples of stabilising G4s with small molecules are often a one-way response and thus targeting of G4s often leads to toxic side effects. In addition, as G4s are found across all cell types, ligands with poor selectivity may lead to unwanted interactions and side effects where healthy tissues are affected in off-target binding. To address the above, photoswitchable ligands can be used with an external light stimulus to control the on/off activity of G4 binding with high spatiotemporal control.

This work describes the development of a new class of G4 photoswitchable ligands known as diazocines. A small library of diazocines are synthesised and fully characterised and their potential as G4 ligands is evaluated with various techniques such as Förster resonance energy transfer (FRET) melting assays, UV-Visible spectroscopy, CD spectroscopy, NMR spectroscopy and MD simulation.

Additionally, the antibacterial activity of azobenzene ligands towards E. coli was investigated and a potential link with G4 stabilisation as a mode of action was explored. 17 putative quadruplex sequences that were initially identified in proteomics and bioinformatics studies, were shown to form G4s in potassium phosphate buffers. The stabilisation by the addition of ligands was also probed by spectroscopic techniques, which uncovered interesting conformational changes that could be insightful for the future study of these dynamic structures.
Date of Award7 May 2024
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorM C Galan (Supervisor) & Adrian J Mulholland (Supervisor)


  • G-quadruplex
  • G4
  • photoswitches
  • azobenzene
  • diazocine

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