Di Porzio, Anna (2022) Targeting of noncanonical nucleic acid structures for therapeutic intervention and biological investigation. [Tesi di dottorato]

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Abstract

G-quadruplex (G4) structures fall among the most extensively studied noncanonical DNA/RNA conformations, with the current knowledge suggesting that they might play an integral part in many biological processes, including transcriptional regulation, telomeric maintenance, malignant transformation, and cancer development. In the last decade, mounting attention has been also focused on i-motif (iM) structures. Even though the structural aspects of iM formation, the factors leading to its stabilization, and its putative biological roles have been recently reviewed and discussed by the scientific community, there is still much to know about such noncanonical nucleic acid conformation. This PhD project aimed, on the one hand, at providing a more in-depth knowledge about the i-motif structures and, on the other hand, at identifying and developing new molecular tools able to target alternative nucleic acid secondary structures for either therapeutic intervention or biological investigation. Particularly, the thesis has been subdivided as follow: Chapter 1 provides a general description of nucleic acids and noncanonical DNA/RNA conformations, stressing on their structural features and biological roles. Chapter 2 offers an overview of the main methodologies employed in the herein presented studies. Chapter 3 includes two detailed investigations on iM structures. The first one is a systematic study to simultaneously analyze the effect of pH, cation type, and cation concentration (and their possible interactions) on the formation of an i-motif structure in vitro. The second one uses multivariate data analysis to bring out valuable structural information on i-motif DNA from circular dichroism and thermal difference spectra. Chapter 4 describes new G4-targeting compounds that we identified or rationally designed and synthesized as potential anti-cancer agents. In Chapter 5, new molecules are reported that might be used as tools to clarify the biological roles of G4 and iM structures and their intriguing relationship. The last section of this PhD thesis collects the general conclusions. Finally, the Appendix reports the published scientific articles as cited throughout the thesis. Paper IV is not included since the Manuscript is still in preparation and has not been submitted at the present time.

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