Development of Two Novel Families of Platinum(Ii) Coordination Complexes for Nucleic Acid Recognition

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Manas, Katie
Synthesis, Nucleic Acid Recognition, Platinum(II) Complexes, Heterocycles, Guanine Quadruplex
Nucleic acids can adopt shapes other than the widely recognized double helix duplex form of DNA. In fact, they can also self-assemble into alternative higher order architectures, such as guanine quadruplexes (G4s). These four stranded assemblies have risen to prominence as promising drug targets as a result of their demonstrated relevance and enrichment in genomic regions involved in cancer, neurodegenerative conditions, bacterial infections, and viral infections. Therefore, targeting G4s using small molecule binders has rapidly grown as a field of research due to the potential therapeutic effect on a range of possible diseases. The overall objective of the MSc research presented herein is to synthesize and characterize novel G4 binders based on a platinum(II) coordination platform with high G4 affinity, with the future goal of assessing their G4-recognition and stabilization abilities. The first family of novel complexes contains an aromatic platform functionalized with moieties that could potentially improve G4 binding affinity and/or specificity through interactions with loops or grooves. Synthesis of the ligands and complexes is described, as well as any observed luminescent properties. Promisingly, preliminary biophysical information from UV-Vis titrations of two of the synthesized complexes qualitatively demonstrated strong interactions with a G4-forming DNA sequence. The second family of G4 binders involves tri- and tetradentate ligands and corresponding Pt(II) complexes with controlled sequences of heteroaromatic units that provide the opportunity to explore potential differences in G4 interactions between alternative binder footprints. The investigation of various synthetic methods and challenges overcome are described in the journey to synthesize and characterize the final polydentate complexes. The two novel families of Pt(II) complexes developed in this thesis will lay the foundation for future biophysical studies with biologically relevant G4 sequences, to evaluate their performance as promising binders for G4 recognition.
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