The design and synthesis of DNA binding compounds targeting DNA junctions

Kamperi, Victoria (2026) The design and synthesis of DNA binding compounds targeting DNA junctions. Doctoral thesis, University of East Anglia.

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Abstract

The uncontrolled proliferation of cancer cells leads to the upregulation of DNA repair pathways, highlighting this process as an interesting target for cancer therapy. DNA junctions are secondary structures that form during DNA repair. Four-way junctions assemble during homologous recombination, a major DNA repair pathway responsible for the repair of double-strand DNA breaks. N,N’-Dimethylaminoethyl 9-aminoacridine-4-carboxamide dimers linked through a flexible methylene chain are cytotoxic compounds that can bind to DNA through intercalation. They have also been shown to bind to four-way junctions via a novel mechanism, although this imparted little selectivity over double-stranded DNA.

In this thesis, the design and synthesis of twelve acridine-based dimeric compounds is presented, including six novel small molecules designed with restricted flexibility to bind across four-way junctions via duplex-to-duplex DNA crosslinking. DNA binding to duplex DNA and four-way junctions was assessed through a displacement assay and electrophoretic mobility shift assays. The effect on the stability of the 4WJ upon ligand binding was investigated through melting experiments, further determining 4WJ selectivity in the presence of secondary DNA structures.

Furthermore, the synthesis of two novel acridine trimers is reported, targeting three-way DNA junctions, designed to bind to multiple sites of the junction simultaneously. Gel electrophoresis studies showed that the compounds can promote the formation of a three-way junction at concentrations as low as 1.56 μM, whereas they have no effect on four-way junctions at this concentration. Additionally, the trimers cause a significant increase in the stability of a three-way junction upon binding (ΔTm = 30 °C, 10 μM).

The designed acridine dimers and trimers were evaluated for cellular efficacy in leukaemia, melanoma and pancreatic cancer cell lines. A cell assay indicated synergy between the acridine dimers and DNA repair inhibitors in cancer cells, offering a potential novel therapeutic approach in cancer treatment.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Chris White
Date Deposited:	11 Jun 2026 08:32
Last Modified:	11 Jun 2026 08:34
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103347
DOI:

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