Advanced Spectroscopic Studies of Structurally Diverse DNA Systems Towards New Therapeutics and Diagnostics

Deoxyribose nucleic acid (DNA) is the structural molecule of life coding for all cellular function. Therefore, it is the primary target for an array of malignant genetic diseases. Cytosine and guanine rich DNA sequences form non-canonical i-motif and G-quadruplex structural knots, which are prevalent in overexpressed cancer cells. These structures comprise readily oxidisable base stacking regions that have a highly susceptible to induced photodamage. The development of small molecules that interact with these structures deepens our understanding of non-canonical photostability and enable targeted DNA photodamage, as a direct route to cancer therapy. In Chapter 2, light activated Osmium polypyridyl have been used to signal the presence of specific quadruplex and AT/GC steps in DNA, due to their unique emission sensitivity to the DNA binding environment. These probes absorb red light, allowing deeper tissue penetration and enhanced practicability in photodynamic therapy. Additionally, their biologically independent NIR emission at 750 nm avoids autofluorescence, enabling improved cellular detection. These diverse probes show the ability of transition metal complexes as DNA targeting diagnostic probes and photo-triggered therapeutic drugs with potential use in malignant genetic disease detection and treatment. In Chapter 3, ruthenium polypyridyl’s have been synthesised to target these structures, by adapting the strongly binding Dipyrido[3,2-a:2',3'-c]phenazine (dppz). To improve quadruplex sequence targeting. This chapter highlights their ability to target pre-defined areas of DNA and act as base specific reporters on targeted DNA areas. The inclusion of Stark reporter (nitrile groups) further report on the binding environment within hydrophobic quadruplex binding pockets. In Chapter 4, the π-deficient 1,4,5,8-traazaphenanthrene (TAP) ligand has been coordinated to the Ruthenium centre to improve the excited state oxidation potential of the complex and advance photo-activated guanine oxidation. Spectroscopic DNA titrations have assessed the DNA binding strength of the complex in solution and complementary time-resolved infrared (TRIR) studies have selectively probed the binding modalities and oxidising ability. Finally chapter 5, involves the ultrafast study of photophysical relaxation pathways within epigenetic DNA systems following UV excitation. Exposure of DNA to UV radiation can trigger deleterious effects and mutation forming photophysical pathways, with profound biological consequences. This chapter details the excited states formed within non-canonical bases and their subsequent decay pathways. This chapter initially performs a systematic study from simple nucleotide units to trinucleotides, progressing to biologically relevant oligonucleotide and i-motif structures.