Pagano, Alessia (2018) Investigating non-canonical nucleic acid structures and their interaction with potential anticancer drugs. [Tesi di dottorato]

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Abstract

The outstanding structural polymorphism of DNA allows for the formation of non-canonical secondary structures, such as G-quadruplexes (G4s), G-triplexes (G3s) and i-motifs. G4 and i-motif structures are found within important functional genomic regions such as telomeres and gene promoters. In particular, they are localized within the promoter regions of several proto-oncogenes, whose overexpression leads to malignant transformation, where they play a major role in the regulation of transcription. In many cases, the biological consequence of non-canonical secondary structure formation in the promoter element is gene silencing. For this reason, the search for ligands able to bind and stabilize G4s and/or i-motifs is pharmacologically very important to develop new anticancer strategies. In this PhD thesis, a series of studies have been carried out with the aim of investigating these non-canonical nucleic acid structures and their interaction with potential anticancer drugs. Such studies have led to the discovery of new and selective G4 ligands (Chapter 3). Chapter 4 deals with the tandem application of virtual screening along with experimental investigations, that led to discover the first dual G-triplex/G-quadruplex stabilizing compound. In Chapter 5, biophysical techniques have been employed to demonstrate that some well-known G4 ligands are also able to interact with i-motif structure. The last section of this PhD thesis deals with a study conducted in Dr. Vincenzo Abbate’s laboratory at King’s College London (UK). It concerns the design and synthesis of a new class of gallium chelator to be employed in the development of chemically-modified nucleic acid aptamers to be used as theranostics.

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