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Construction of template-assembled pyrimidine-based quartets and quadruplexes Hui, Benjamin Wei Qiang
Abstract
Pyrimidine-based quartets and quadruplexes are unstable and thus are rarely encountered in nature. Uracil (U) and thymine (T) quartets in the solution state have only been found as part of pre-existing G-quadruplex scaffolds and the corresponding quadruplexes have not been reported. Studies on such systems might shed light on their role in nucleic acid topology and stability. This thesis describes the assembly and structural characterization of these motifs in vitro as a result of grafting the respective nucleosides onto resorcinol-based cavitands. These rigid macrocycles serve as molecular templates on which these motifs are preorganized. Reduction of entropic loss improves thermodynamic stability and promotes self-assembly. A convergent synthetic strategy was employed for accessing these cavitand-nucleoside conjugates. Cavitands and nucleosides were prepared separately using established literature methods, and the final coupling step of the two components entailed a copper (I)-catalyzed azide-alkyne cycloaddition, or a "click" reaction. NMR spectroscopy was used extensively in signal assignment, structure elucidation and oligomeric state analysis. CD spectroscopy was employed in some cases to provide further confirmation of defined structure. Findings indicated the spontaneous self-assembly of a U-quartet in CDCl3 at both 25 ºC and –20 ºC. In the presence of a metal cation (Sr²⁺), symmetric homodimerization of two U-quartets occurs at 25 ºC. The corresponding U-quadruplex unit was identified in DMSO-d₆ at 25 ºC. The T-quartet was shown to be nonexistent at 25 ºC, but assembles at a low temperature of –40 ºC. iii No evidence for metal cation uptake was found at 25 ºC. Assembly of the T-quadruplex was confirmed in DMSO-d₆ at 25 ºC. In all of these systems, stacking of the nucleobase and triazole linker rings was indicated suggesting π-stacking interactions to be a significant contributor to overall stability.
Item Metadata
Title |
Construction of template-assembled pyrimidine-based quartets and quadruplexes
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2014
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Description |
Pyrimidine-based quartets and quadruplexes are unstable and thus are rarely encountered in
nature. Uracil (U) and thymine (T) quartets in the solution state have only been found as part of
pre-existing G-quadruplex scaffolds and the corresponding quadruplexes have not been reported.
Studies on such systems might shed light on their role in nucleic acid topology and stability. This
thesis describes the assembly and structural characterization of these motifs in vitro as a result of
grafting the respective nucleosides onto resorcinol-based cavitands. These rigid macrocycles
serve as molecular templates on which these motifs are preorganized. Reduction of entropic loss
improves thermodynamic stability and promotes self-assembly.
A convergent synthetic strategy was employed for accessing these cavitand-nucleoside
conjugates. Cavitands and nucleosides were prepared separately using established literature
methods, and the final coupling step of the two components entailed a copper (I)-catalyzed
azide-alkyne cycloaddition, or a "click" reaction. NMR spectroscopy was used extensively in
signal assignment, structure elucidation and oligomeric state analysis. CD spectroscopy was
employed in some cases to provide further confirmation of defined structure.
Findings indicated the spontaneous self-assembly of a U-quartet in CDCl3 at both 25 ºC and –20
ºC. In the presence of a metal cation (Sr²⁺), symmetric homodimerization of two U-quartets
occurs at 25 ºC. The corresponding U-quadruplex unit was identified in DMSO-d₆ at 25 ºC. The
T-quartet was shown to be nonexistent at 25 ºC, but assembles at a low temperature of –40 ºC.
iii
No evidence for metal cation uptake was found at 25 ºC. Assembly of the T-quadruplex was
confirmed in DMSO-d₆ at 25 ºC. In all of these systems, stacking of the nucleobase and triazole
linker rings was indicated suggesting π-stacking interactions to be a significant contributor to
overall stability.
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Genre | |
Type | |
Language |
eng
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Date Available |
2014-07-17
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivs 2.5 Canada
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DOI |
10.14288/1.0167249
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2014-09
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivs 2.5 Canada