Abstract
G-quadruplexes (G4s) are non-canonical secondary structures of nucleic acids, which are formed in guanine-rich sequences of DNA or RNA. G4s are biologically relevant in various nucleic acid replicative processes and gene expression pathways. The binding of G4 selective ligands to G4s over duplex DNA has resulted in anticancer, antibacterial, antiviral and antiparasitic activity, due to the disruption of key biological processes mediated by G4s and G4-interacting proteins. Thus, the identification of new ligands to target G4s is important to study the role and function of G4s and for the development of disease treatments.A tri-functional probe containing a G4-binding unit, photocrosslinker unit and a biotin unit has been designed and its synthesis attempted to enable covalent crosslinking of G4s and G4-interacting proteins. The diazocine G4 ligand moiety allows for selective ligand-G4 binding over duplex DNA, whilst photoswitching between E- and Z- photoisomers aims to achieve on/off binding control to the G4 target. The benzophenone photocrosslinker unit can be photoirradiated to covalently crosslink to nearby G4s or G4-interacting proteins. The biotin unit provides a substrate for streptavidin-based recapture assays, whereby the subsequent characterisation of the covalently captured species could contribute to the understanding of G4-mediated biological processes or lead to the identification of new therapeutic targets.
Dithienylethene (DTE)-based ligands have been identified as selective binders to G4s over duplex DNA with anticancer activity. It has been shown that small modifications to the ligand structure has implications with regards to the binding affinity to G4s. Moreover, the ability of DTEs to photoswitch between open and closed photoisomers makes them attractive ligands for photopharmacological therapeutics. This work investigates a novel DTE scaffold decorated with pyridinium side chains via amide bridges, to evaluate the photochemical properties of both open and closed isomers and G4 binding ability compared to the originally reported pyridinium DTE, which featured the pyridinium motifs directly connected to the DTE scaffold. The anticancer activity of the ligand was explored towards HeLa cervical cancer cells, further highlighting the potential of DTEs as potential tools in photopharmacological therapeutics.
| Date of Award | 13 May 2025 |
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| Original language | English |
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| Supervisor | M C Galan (Supervisor) |