PROSPECTIVE BINDER SYNTHESIS AND STRUCTURAL STUDIES OF GUANINE QUADRUPLEXES
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Authors
Marsh, Jevon
Date
Type
thesis
Language
eng
Keyword
Nucleic Acids , Quadruplexes , Carbamate Synthesis , Nuclear Magnetic Resonance Spectroscopy
Alternative Title
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.
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CC0 1.0 Universal
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
CC0 1.0 Universal