Photoresponsive ligands for G-quadruplex DNA

  • Michael P O'Hagan

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

G-quadruplexes are four-stranded nucleic acid secondary structures formed from sequences rich in guanine. These structures display potential as therapeutic targets and as the basis of functional materials. Both of these applications rely on exerting control over the formation of these polymorphic architectures. Small molecule ligands can exert this control by selective stabilisation of the folded structures, but normally only allow a one-way response as their delivery to a system cannot be readily reversed. Photoresponsive ligands offer an opportunity to circumvent this limitation, since their activity may be switched on or off with spatiotemporal precision based on a change in the ligand structure upon irradiation with light. In therapy, this level of control could allow the activity of a G-quadruplex targeting drug to be restricted to a desired site of action, such as a tumour, in an approach known as photopharmacology. Meanwhile, the possibility to control nucleic acid/ligand assemblies reversibly could be deployed in the development of new responsive materials. Despite these opportunities, scant attention to date has been devoted towards the development of photoresponsive G- quadruplex targeting molecules.
This thesis reports the investigation of two photoresponsive scaffolds, stiff-stilbene and dithienylethene, as the basis of novel G-quadruplex ligands. The design, synthesis and optimisation of candidate ligands derived from these chromophores is described. The ligands are evaluated as G-quadruplex binding agents by means of fluorescence-based melting assays, UV/visible spectroscopy, circular dichroism spectroscopy, NMR spectroscopy and molecular dynamics simulations. The bioactivity of the ligands against a small panel of mammalian cells and parasitic organisms is also investigated. The photochemistry of the ligands in physiologically-relevant conditions is explored and the respective photoresponses deployed to control G-quadruplex structure, ligand binding mode and cytotoxicity.
Date of Award29 Sep 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorM C Galan (Supervisor) & Juan C Morales (Supervisor)

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