PROSPECTIVE BINDER SYNTHESIS AND STRUCTURAL STUDIES OF GUANINE QUADRUPLEXES

Abstract

Guanine Quadruplex (G4) architectures have been a hot research topic for decades, claiming much of their fame due to their demonstrated potential for regulating various diseases, such as cancer, infections, and neurological disorders, at both the level of DNA and RNA. As a result of their demonstrated importance and relevance to medicine and future treatment options for patients, the development of a series of binders that can achieve selective stabilization of these architectures is highly sought after. The objective of this MSc dissertation is to synthesize a series of binders for future assessment of their interactions with higher order G4 architectures. First, synthetic routes for developing carbamate-functionalized naphthyridine derivatives were considered in accordance with literature procedures to assess how naphthyridine-based molecules would interact with G4 architectures, more specifically, whether they would disrupt or provide enhanced stability for G4s. Two methods for introducing carbamates into the binders’ design were considered, and one determined to be optimal. Second, a synthetic route for developing a binder for stabilizing the G4 formed in the promoter region of the Rearranged After Transfection (RET) gene is discussed. A family of platinum-based binders inspired by previous work in the Petitjean lab is described, and their synthetic route presented. Lastly, an introduction to the use of Nuclear Magnetic Resonance Spectroscopic methods in the elucidation of quadruplex structures is described. This study investigates the very first monomolecular RNA G4 architecture that is formed by the B-Cell Lymphoma/Leukemia 2 (BCL-2) proto-oncogene, reporting the structural assignment of all guanine nucleobases within this architecture. The body of work described herein, namely the synthetic methodologies described and the elucidation of an RNA G4 architecture, lays the foundation for the future development of selective G4 binders. As a result of the regulatory roles of G4s in diseases such as cancer, the binders discussed will inspire the creation of more effective treatment options for future patients.