Item – Theses Canada

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OCLC number
911144704
Link(s) to full text
LAC copy
Author
Castor, Katherine,
Title
Transition metal complexes as G-quadruplex DNA binders
Degree
Ph. D. -- McGill University, 2014
Publisher
[Montreal] : McGill University Libraries, [2014]
Description
1 online resource
Notes
Thesis supervisor: Hanadi Sleiman (Supervisor).
Includes bibliographical references.
Abstract
"Guanine quadruplexes are non-canonical secondary structures that can form in guanine-rich DNA and are stabilized by monovalent cations present in physiological conditions. Bioinformatics studies have identified putative G-quadruplex forming sequences throughout the human genome, in the telomeres and promoter regions of oncogenes. Small molecules that promote the folding of these G-rich sequences into a G-quadruplex structure can result in biologically relevant phenomena that have profound effects on cancer cell proliferation, generally through telomerase inhibition and suppression of oncogene expression, thereby accomplishing one of the main goals of chemotherapy: to halt tumor growth. G-quadruplex forming sequences vary in their nucleobase composition, which allows for topologically distinct monomeric structures. These varying topologies present a means of targeting one polymorph rather than all, which permits site-specific therapies for small molecules that can discriminate between the structures. To date, both organic and inorganic compounds with varying degrees of efficacy in their targeting of this DNA structure have been reported. From this wealth of empirical data, it has been shown that small molecules can bind to G-quadruplexes most often through end [pi]-stacking, although interaction with the loops and groove environments can be permitted with extended side-chains from a highly aromatic core. Herein, we present efforts made towards the creation of transition metal-based G-quadruplex binders consisting of phenanthroimidazole ligands coordinated to platinum(II) and iridium(III) centers. These complexes are ideally suited for recognition of G-quadruplex motifs due to their electron-poor heteroaromatic nature and inherent positively-charged metal center for optimal [pi]-stacking with the G-tetrad surface. Through the use of molecular modeling, biophysical (circular dichroism, fluorescence intercalator displacement assays, surface plasmon resonance, continuous variation analysis, fluorescence binding assays), biological (telomerase inhibition assays, cell cytotoxicity assays, mRNA levels analysis, western blotting), and electrochemical (cyclic voltammetry, electrogenerated chemiluminescence) techniques, we study the properties of these complexes and their interaction with biologically relevant G-quadruplexes."--
Other link(s)
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digitool.library.mcgill.ca