Abstract
G-quadruplexes (G4s) are of significant interest for oncological and antiviral applications. Substantial work has gone into exploring G4s as alternative chemotherapeutic targets, highlighting this as a promising area of research. Within this field, a substantial portion of the reported studies have involved the use of small molecule ligands to selectively target G4s.A property ubiquitous in nature, chirality is of supreme importance in chemistry. Chirality is especially prevalent in pharmaceutical drug design. It is well documented that enantiomers can have vastly different biological properties, and the interaction of chiral compounds underpins many processes that are fundamental to life. Within the field of G4 chemistry, there is a surprising lack for consideration of the implications of chirality in the design of G4-ligands. This thesis hopes to address the implications of chiral design with G4 ligands and explore how iterative changes to G4-ligands can alter how the ligands interact with different G4s.
Chapter one introduces G4 chemistry, discussing the properties of G4s, the effects of different topologies and the sequences used in this study. It will also provide a literature overview surrounding G4-ligands and their chemistry. In this section, different classes of ligand are discussed and their varied interactions with G4s both in vitro and in cellulo.
Chapter two surrounds initial studies performed with a small library of naphthalenediimide (NDI) ligands functionalised with B-amino acids, detailing the synthetic route, molecular docking techniques and variable temperature studies. The ligands showed selectivity for the c-KIT1 sequence, with evidence of stereospecific recognition between pairs of enantiomers for multiple sequences within the dataset.
Chapter three focuses on the evolution of the previous NDI scope that has been further functionalised with N1,N1-dimethylpropane-1,3-diamine, generating so-called ‘NDI-amides’. The development of a reliable synthetic methodology is detailed for the generation of both a- and B-amino acid-derived NDI amides. With G4s, the enhanced binding properties of the NDI-amides is discussed, along with the use of high-level modelling techniques to rationalise the stereospecific binding behaviour observed. Further detail is given for the human telomeric G4 sequence which undergoes a conformational change with the NDI-amides. The NDI-amide-G4 interactions are probed with 1H NMR, providing structural evidence of the binding of the G4 by the NDI-amide.
Chapter four considers RNA G4s and their interaction with the above NDI-amides. An exploration of the differences in binding by the same sequence in the RNA form versus the equivalent DNA form is probed, highlighting the NDI-amides apparent preference for binding DNA G4s.
Chapter five details the development of a series of benzodifuran ligands for G4s, describing the development of a reliable synthetic methodology for amino acid-functionalised benzodifurans (BDFs). The BDFs’ stabilising ability with both DNA and RNA G4s is probed, exploring how a change in the core of the molecule can change how the ligand interacts with the G4. The studies highlighted a selective preference of the BDFs for c-KIT1, showing the potential for tuneable properties with G4-ligands.
The final chapter encompasses the use of cyanine dye molecules in the generation of chiral J aggregates. The chiroptical study of solution-phase materials is explored along with the dependence on vortices to give tuneable properties of two different cyanine dye J-aggregate solutions. Measurement of circularly polarised luminescence and the tuneability of a solution of 5,6-dichloro-2-[[5,6-dichloro-1-ethyl-3-(4-sulfobutyl)-benzimidazol-2-ylidene]-propenyl]-1-ethyl-3-(4-sulfobutyl)-benzimidazolium hydroxide is also explored in this chapter.
| Date of Award | 8 Oct 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Dan Pantos (Supervisor) & Simon Lewis (Supervisor) |